We focus on the identification of genetic susceptibility variants associated with com-22Figure: Mosaic chromosomal alterations (mCAs) and precancerous cell expansion are inevitable when humans become oldplex traits and on understanding their biological roles by using integrative analyses of epigenome, transcriptome and chromatin accessibility data. We are also interested in acquired mutations as strong driving forces of phenotypes. We will then deliver these genetic findings to patients as part of our ongoing translational research efforts.Dozens of genome-wide association studies in our laboratory have identified thou-sands of susceptibility loci for multiple complex traits. Most of these accomplishments were viewed in the field as the largest ever human genetic analyses for non-Europeans (available at http://jenger.riken.jp/en/). Our analyses have clarified the similarity and differences between populations with regard to genetics of the traits. We performed downstream analyses to un-derstand the biological background of traits and found that trait-relevant cell types can be linked by applying integrative analysis of genetic and epigenetic data. In 2020, we successfully identified somatic chromosomal alterations in autosomes (mosaic chromosomal alterations, mCAs) from DNA microarray data. We identified a surprisingly high number of mCAs (more than 33,000) in 180,000 participants. We observed that more subjects carried mCAs accord-ing to their age and more than 40% of subjects in their 90s were positive for mCAs, strongly indicating that mCAs are inevitable when we become aged (Figure). We also found that mCAs in the T-cell receptor (TCR) were more frequently observed, but ones in the B-cell re-ceptor (BCR), were less frequently observed in Japanese than UK populations. Since chronic lymphocytic leukemia (CLL), a type of of B-cell leukemia, is common in Europeans but rare in Japanese and T-cell leukemia is common in Japanese but rare in Europeans, the differences in genes harbored in mCAs could foreshadow epidemiological differences in hematopoietic malignancies between Japan and Europe. Furthermore, three different mutational precursors of CLL (including trisomy 12, loss of chromosomes 13q, and 13q copy-neutral loss of hetero-zygosity) were between two and six times less common among Japanese individuals. This sug-gests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent CLL. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28–91).We are moving into two new major research fields. One is to focus on somatic events and to use whole genome sequencing analysis to detect rare variants, which represent strong candidates to explain population differences in the genetics of the traits, especially somatic events, and to enable the future Genomic Medicine for East Asians. The second is to employ deep learning techniques to predict the biological consequences of trait-relevant variants. Ge-netic evidence, in conjunction with epigenome, transcriptome, and other cellular multi-omics data, may lead to the discovery of novel biological principles. This project will proceed more efficiently as a result of collaborations with other IMS laboratories.Recent Major PublicationsTerao C*, Suzuki A, Momozawa Y, Akiyama M, Ishigaki K, Yamamoto K, Matsuda K, Murakami Y, McCarroll SA, Kubo M, Loh PR, Kamatani Y. Chromosomal alterations among age-related hematopoietic clones in Japan. Na-ture 584, 130-135 (2020)Koyama S, Ito K, Terao C, Akiyama M, Horikoshi M, Momozawa Y, Matsunaga H, Ieki H, Ozaki K, Onouchi Y, Takahashi A, Nomura S, Morita H, Akazawa H, Kim C, Seo JS, Higasa K, Iwasaki M, Yamaji T, Sawada N, Tsugane S, Koyama T, Ikezaki H, Takashima N, Tanaka K, Arisawa K, Kuriki K, Naito M, Wakai K, Suna S, Sakata Y, Sato H, Hori M, Sakata Y, Matsuda K, Murakami Y, Aburatani H, Kubo M, Matsuda F, Kamatani Y, Komuro I. Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease. Nat Genet 52, 1169-1177 (2020)Amariuta T, Ishigaki K, Sugishita H, Ohta T, Koido M, Dey KK, Matsuda K, Murakami Y, Price AL, Kawakami E, Terao C, Raychaudhuri S. Improving the trans-ancestry porta-bility of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements. Nat Genet 52, 1346-1354 (2020)Invited presentationsTerao C. “Genetic analyses and translational studies for rheumatoid diseases” Symposium, The 65th Annual Meeting of the Japan Society of Human Genetics (Japan/Online) November 2020Terao C. “Genetic data informs pathophysiology, treat-ment targets and risk of disease onset in rheumatic diseases” The 7th JCR Basic Research Conference (Tokyo, Japan) October 2020Terao C. “Genetics of cardiovascular diseases and clinical application of genetic findings” The 4th JCS Council Fo-rum on Basic CardioVascular Research (Nagoya, Japan) September 2020Terao C. “Construction of database and analyses of data for rheumatic diseases under the viewpoint of physician scientist” Meet The Expert, Japanese College of Rheuma-tology (JCR) symposium (Japan/Online) August 2020Terao C. “Construction and application of database for rheumatic diseases under the viewpoint of physician sci-entist” The 10th Rheumatology Education Inter League REIL (Osaka, Japan) January 2020Laboratory for Statistical and Translational GeneticsTeam Leader: Chikashi Terao
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