Our overall long-term goal is to realize precision medicine by finding vari-20ants, especially population-specific ones, with strong effect sizes. We are integrating germline and somatic information including gene expression, understanding the basis of complex traits, and constructing accurate evaluation models of the current physiological status of the body and prediction models of diseases and outcomes.To detect variants with strong effect sizes, we developed MOPLINE, a com-putational algorithm to confidently call structural variations (SV) using short-read whole-genome sequencing (WGS) data. MOPline stably detected ~16,000 SVs per individual, which is over 2-fold higher than found in previous large-scale projects, while exhibiting comparable statistical quality metrics. We imputed SVs from 181,622 Japanese individuals and found novel associations for diseases and quantitative traits. SVs detected by MOPLINE could separate sequence data from different populations into different clusters, suggesting population-specific SVs.We also addressed genetic selection signals in the Japanese population. We analyzed genetic data from 20,366 Japanese individuals from the two major Japanese subpopulations (Hondo and Ryukyu). While significant signals were observed in the major histocompatibility complex region in both subpopula-tions, the lead variants differed, tagged different HLA haplotypes and demon-strated substantial allele frequency differences between Hondo and Ryukyu. Notably, the haplotype selected in Ryukyu, where human T lymphotropic virus type 1 (HTLV-1) is prevalent, is reported to confer protective effects against HTLV-1-associated myelopathy/tropical spastic paraparesis. We are planning to connect population-specific variants with selection signatures.We also showed a successful example of integrating gene expression regulation with genetic data. The variants associated with prostate cancer (PrCa) are strong-ly enriched in androgen receptor (AR) binding sites in the normal prostate. A polygenic risk scores (PRS) analysis restricted to statistically finemapped variants in AR binding sites showed that, among cancer-free subjects, individuals with a PRS in the top 10% have a much higher risk of future death from PrCa (Figure).Figure: PRS based on AR information showed good prediction of future death due to PrCa in initially cancer-free subjectsThe comparison of survival rates between the top 10% of PRS and the bottom 50% is based on the variants located in androgen receptor binding sites. The x-axis indicates the time (years) from initial recruitment and the y-axis indicates the cumulative survival rate of PrCa. While not shown in the figure, the PRS based on AR information showed better predictive value than that by the conventional method.Recent Major PublicationsLiu X, Matsunami M, Horikoshi M, Ito S, Ishikawa Y, Su-zuki K, Momozawa Y, Niida S, Kimura R, Ozaki K, Maeda S, Imamura M, Terao C*. Natural Selection Signatures in the Hondo and Ryukyu Japanese Subpopulations. Mol Biol Evol 2023;40 (10)Kosugi S, Kamatani Y, Harada K, Tomizuka K, Momozawa Y, Morisaki T, The Biobank Japan Project, Terao C*. Detec-tion of trait-associated structural variations using short read sequencing. Cell Genomics 2023;3 (6)Ito S, Liu X, Ishikawa Y, Conti DD, Otomo N, Kote-Jarai Z, Suetsugu H, Eeles RA, Koike Y, Hikino K, Yoshino S, Tomizuka K, Horikoshi M, Ito K, Uchio Y, Momozawa Y, Kubo M, BioBank Japan Project, Kamatani Y, Matsuda K, Haiman CA, Ikegawa S, Nakagawa H, Terao C*. Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects. Nat Commun 2023;14 (1)* corresponding authorInvited presentationsTerao C. “Deciphering human complex traits using static and dynamic genomic information” invited talk at Shanghai Jiao Tong University (Shanghai, China) Octo-ber 2023Terao C. “Biobank Japan: Roles of Genetics for Discovery Research” International Round-table Meeting of Popula-tion Biobanks (Beijing, China) September 2023Terao C. “Deciphering human complex traits using popu-lation-specific germline and somatic genetic variations” Human Technopole Seminar (Milan, Italy) June 2023Terao C. “Decoding human complex traits and cancers by integrative genomics” IFOM Seminar (Milan, Italy) June 2023Terao C. “Pathophysiology and disease prediction of spinal diseases by genetic epidemiological analysis” The 52nd Annual Meeting of the Japanese Society for Spine Surgery and Related Research (Sapporo, Japan) May 2023Laboratory for Statistical and Translational GeneticsTeam Leader: Chikashi Terao
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