RIKEN IMS AnnualReport 2020
34/98

CDEFAGHAutoimmune diseases are thought to arise from the interaction of genetic 0.90.70.50.30.128CAGE ‐Interaction between enhancer and promoterRisk SNPenhancerPromoter/enhancer QTLCAGE +expression‐QTL (eQTL)promoterATAC‐QTLHistone‐QTLGWAS VariantsMulti‐omics data from each cell typeBCAGEsequencing:enhancer/promoterATAC‐seq:open chromatin ChIP‐seq:modified histones RNA‐Seq:gene expression levelsMicroC‐seq:3D‐chromatin interactionIntegrated multi‐omics dataGenomic Landscape by interpretation of multi‐omics dataFigure: Functional genetics of autoimmune dis-easesand environmental factors. Improvements in commercial arrays since 2007 have led to the development of the current form of genome-wide associa-tion studies (GWASs). GWASs rely on single-nucleotide polymorphisms (SNPs) and haplotype blocks. The loci associated with disease susceptibility can then be determined by comparing variants represented by tag SNPs between patients and controls and identifying those that are significantly different. Genetic risk factors are essentially causative for specific diseases and traits. However, under-standing the biological mechanism of risk from a genetic factor is challenging. Although associations between variants and diseases can be identified, it is dif-ficult to identify the causal variant among multiple variants located on the same haplotype, and experimental validations are needed to determine the functional variants. Furthermore, understanding the biological functions of risk variants is not straightforward, since more than 80% of disease-associated variants are located in non-coding regions of the genome.The capabilities of next-generation sequencing techniques for analyzing the functions of non-coding regions have advanced dramatically in recent years, enabling the comprehensive analysis of enhancers, promoters, histone modifi-cations, and chromatin structures. Analysis of expression quantitative trait loci (eQTL) has been used to investigate how particular variants lead to different expression levels of a particular gene. QTL are DNA markers on a chromo-some that indicate genes involved in a quantitative trait. We are performing functional genomic strategies for integrating GWAS results with the current understanding of specific diseases, mainly focusing on promoters, enhancers, and long non-coding RNAs. We are isolating nearly 30 different lymphocyte subsets from human peripheral blood mononuclear cells of healthy individuals and analyzing genotypes, gene expression and open chromatin regions.We believe that insights gained from these studies will enable us to under-stand precise causal pathogenic processes and develop better strategies to con-trol autoimmune diseases.Recent Major PublicationsSuzuki A, Guerrini MM, Yamamoto K. Functional genom-ics of autoimmune diseases. Ann Rheum Dis 80, 689-697 (2021)Terao C, Suzuki A, Momozawa Y, Akiyama M, Ishigaki K, Yamamoto K, Matsuda K, Murakami Yo, McCarroll SA, Kubo M, Loh P, Kamatani Y. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature 584, 130-135 (2020)Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, Sakaue S, Matoba N, Siew-Kee L, 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, Hirota T, Tamari M, Chayama K, Miki D, Mori M, Nagayama S, Daigo Y, Miki Y, Katagiri T, Ogawa O, Obara W, Ito H, Yoshida T, Imoto I, Takahashi T, Tanikawa C, et al. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet 52, 669-679 (2020)Invited presentationsSuzuki A. “Functional analysis of Peptidylarginine deiminases in rheumatoid arthritis model mice” Annual Meeting of American Society of Human Genetics (USA/Online) October 2020Yamamoto K. “Polygenic diseases, Genome wide as-sociation studies and functional genetics” ISPOR Asia Pacific 2020 (Seoul, Korea/Online) September 2020Yamamoto K. “Integration of genetic information to immune functions” The 12th International Forum on Rheumatoid Arthritis (IFRA 2020) (Beijing, China/On-line) September 2020Laboratory for Autoimmune DiseasesTeam Leader: Kazuhiko Yamamoto

元のページ  ../index.html#34

このブックを見る