Parent-of-origin effect in multiple sclerosis susceptibility

2019 Fiscal Year Research-status Report

• Project/Area Number: 18K07529
• Research Institution: Kyushu University
• Principal Investigator: 磯部 紀子 九州大学, 医学研究院, 准教授 (60452752)
• Co-Investigator(Kenkyū-buntansha): 松下 拓也 九州大学, 大学病院, 講師 (00533001) ; 吉良 潤一 九州大学, 医学研究院, 教授 (40183305)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 多発性硬化症 / 片親起源効果

Outline of Annual Research Achievements

多因子疾患である多発性硬化症（MS）ではゲノムワイド関連解析（GWAS）により200以上のリスク遺伝子領域が同定されたものの、未だ遺伝的要因の大部分は説明できていない（missing heritability）。申請者は、このmissing heritabilityを説明するものとして、由来する親の性別によりMS発症への遺伝子の寄与度が異なる「片親起源効果（parent-of-origin effect）」が病態に重要であると仮説を立てた。
まず、両親および発端者の3名（trio）からなる欧米白人931家系の全ゲノムSNPデータとハプロタイプ情報を用いた最新の多項式モデルによる関連解析で、各SNPのアリルが父（または母）から発端者へ遺伝する頻度が偶然に比べて有意に多いか検定し、アリルが由来する親によるアリルのMS発症への寄与度の違いを検討した。
昨年度はPREMIM/EMIMソフトウェアを用い、非主要組織適合遺伝子複合体領域に存在する200個のMSリスク関連SNPについて、片親起源効果を解析したが、今回は過去のGWASデータを用い、全ゲノム上でMS患者に対し片親起源効果を有する遺伝子領域を探索した。結果、母親起源、父親起源効果とも主要組織適合遺伝子複合体領域でのみゲノムワイド有意性を有した。片親起源効果が示唆された領域（p < 10^-6）では、母親由来片親起源効果では、既知のMリスクS関連領域であるEVI5の他、SCN1A、PR11-3L10.3、父親由来片親起源効果ではPRDM9、CSMD1、FRMD6が挙げられた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

昨年度に引き続き、新規MSリスク関連領域候補の同定を進めることができた。父親由来片親起源効果を介したMSリスク関連遺伝子領域の候補の一つであるPRDM9は、ヒストン修飾に影響を与えることが知られており、エピジェネティックな機構を介したMSリスクへの寄与が示唆された。

Strategy for Future Research Activity

新規に同定したMSリスク関連領域の候補遺伝子について、生物学的寄与機構を含めた考察を進めていく方針である。

Causes of Carryover

ほぼ予定した金額は使用したが、残金が生じたため、次年度に繰り越すこととなった。

Research Products

• [Int'l Joint Research] University of California San Francisco(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: University of California San Francisco
• [Journal Article] Contribution of cortical lesions to cognitive impairment in Japanese patients with multiple sclerosis. (2020)
  • Author(s): Shinoda K, Matsushita T, Nakamura Y, Masaki K, Sakai S, Nomiyama H, Togao O, Hiwatashi A, Niino M, Isobe N, Kira J.
  • Journal Title: Scientific Reports Volume: 10 Pages: 5228
  • Peer Reviewed / Open Access
• [Journal Article] Risk HLA-DRB1 alleles differentially influence brain and lesion volumes in Japanese patients with multiple sclerosis (2020)
  • Author(s): Fukumoto S, Nakamura Y, Watanabe M, Isobe N, Matsushita T, Sakoda A, Hiwatashi A, Shinoda K, Yamasaki R, Tsujino A, Kira J.
  • Journal Title: Journal of the Neurological Sciences Volume: 413 Pages: 116768～116768
  • DOI: 10.1016/j.jns.2020.116768
  • Peer Reviewed
• [Journal Article] Unique HLA haplotype associations in IgG4 anti-neurofascin 155 antibody-positive chronic inflammatory demyelinating polyneuropathy (2020)
  • Author(s): Ogata H, Isobe N, Zhang X, Yamasaki R, Fujii T, Machida A, Morimoto N, Kaida K, Masuda T, Ando Y, Kuwahara M, Kusunoki S, Nakamura Y, Matsushita T, Kira J.
  • Journal Title: Journal of Neuroimmunology Volume: 339 Pages: 577139～577139
  • DOI: 10.1016/j.jneuroim.2019.577139
  • Peer Reviewed
• [Journal Article] Central nervous system-specific antinuclear antibodies in patients with multiple sclerosis (2020)
  • Author(s): Fujii T, Yamasaki R, Miyachi Y, Nagata S, Maimaitijiang G, Nakamura Y, Shinoda K, Matsushita T, Isobe N, Kira J.
  • Journal Title: Journal of the Neurological Sciences Volume: 409 Pages: 116619～116619
  • DOI: 10.1016/j.jns.2019.116619
  • Peer Reviewed
• [Journal Article] Environmental risk factors for multiple sclerosis in Japanese people (2020)
  • Author(s): Sakoda A, Matsushita T, Nakamura Y, Watanabe M, Shinoda K, Masaki K, Isobe N, Yamasaki R, Kira J.
  • Journal Title: Multiple Sclerosis and Related Disorders Volume: 38 Pages: 101872～101872
  • DOI: 10.1016/j.msard.2019.101872
  • Peer Reviewed
• [Journal Article] Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis (2020)
  • Author(s): Zhao Y, Yamasaki R, Yamaguchi H, Nagata S, Une H, Cui Y, Masaki K, Nakamuta Y, Iinuma K, Watanabe M, Matsushita T, Isobe N, Kira J.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Pages: 2160～2169
  • DOI: 10.1073/pnas.1901294117
  • Peer Reviewed
• [Journal Article] Spinal cord involvement by atrophy and associations with disability are different between multiple sclerosis and neuromyelitis optica spectrum disorder (2019)
  • Author(s): Nakamura Y, Liu Z, Fukumoto S, Shinoda K, Sakoda A, Matsushita T, Hayashida S, Isobe N, Watanabe M, Hiwatashi A, Yamasaki R, Kira J.
  • Journal Title: European Journal of Neurology Volume: 27 Pages: 92～99
  • DOI: 10.1111/ene.14038
  • Peer Reviewed
• [Journal Article] Intrathecal cytokine profile in neuropathy with anti‐neurofascin 155 antibody (2019)
  • Author(s): Ogata H, Zhang X, Yamasaki R, Fujii T, Machida A, Morimoto N, Kaida K, Masuda T, Ando Y, Kuwahara M, Kusunoki S, Nakamura Y, Matsushita T, Isobe N, Kira J.
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 6 Pages: 2304～2316
  • DOI: 10.1002/acn3.50931
  • Peer Reviewed / Open Access
• [Journal Article] Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility (2019)
  • Author(s): International Multiple Sclerosis Genetics Consortium.
  • Journal Title: Science Volume: 365 Pages: 6460
  • DOI: 10.1126/science.aav7188
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD (2019)
  • Author(s): Watanabe M, Nakamura Y, Michalak Z, Isobe N, Barro C, Leppert D, Matsushita T, Hayashi F, Yamasaki R, Kuhle J, Kira J.
  • Journal Title: Neurology Volume: 93 Pages: e1299～e1311
  • DOI: 10.1212/WNL.0000000000008160
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-term use of interferon-β in multiple sclerosis increases Vδ1(-)Vδ2(-)Vγ9(-) γδ T cells that are associated with a better outcome (2019)
  • Author(s): Maimaitijiang G, Watanabe M, Shinoda K, Isobe N, Nakamura Y, Masaki K, Matsushita T, Yoshikai Y, Kira J.
  • Journal Title: Journal of Neuroinflammation Volume: 16 Pages: 179
  • DOI: 10.1186/s12974-019-1574-5
  • Peer Reviewed
• [Journal Article] The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States (2019)
  • Author(s): Beecham AH, Amezcua L, Chinea A, Manrique CP, Rubi C, Isobe N, Lund BT, Santaniello A, Beecham GW, Burchard EG, Comabella M, Patsopoulos N, Fitzgerald K, Calabresi PA, De Jager P, Conti DV, Delgado SR, Oksenberg J, McCauley JL.
  • Journal Title: Multiple Sclerosis Journal Volume: in press Pages: in press
  • DOI: 10.1177/1352458519863764
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation (2019)
  • Author(s): Didonna A, Canto E, Shams H, Isobe N, Zhao C, Caillier S, Condello C, Yamate-Morgan H, Tiwari-Woodruff SK, Mofrad MRK, Hauser SL, Oksenberg JR.
  • Journal Title: Journal of Autoimmunity Volume: 101 Pages: 56～69
  • DOI: 10.1016/j.jaut.2019.04.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Discriminative clinical and neuroimaging features of motor-predominant hereditary diffuse leukoencephalopathy with axonal spheroids and primary progressive multiple sclerosis: A preliminary cross-sectional study (2019)
  • Author(s): Saitoh B, Yamasaki R, Hiwatashi A, Matsushita T, Hayashi S, Mitsunaga Y, Maeda Y, Isobe N, Yoshida K, Ikeda S, Kira J.
  • Journal Title: Multiple Sclerosis and Related Disorders Volume: 31 Pages: 22～31
  • DOI: 10.1016/j.msard.2019.03.008
  • Peer Reviewed
• [Journal Article] A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis (2019)
  • Author(s): International Multiple Sclerosis Genetics Consortium.
  • Journal Title: Nature Communications Volume: 10 Pages: 2236
  • DOI: 10.1038/s41467-019-09773-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cerebrospinal fluid cytokine/chemokine/growth factor profiles in idiopathic hypertrophic pachymeningitis (2019)
  • Author(s): Zhang X, Fujii T, Ogata H, Yamasaki R, Masaki K, Cui Y, Matsushita T, Isobe N, Kira J.
  • Journal Title: Journal of Neuroimmunology Volume: 330 Pages: 38～43
  • DOI: 10.1016/j.jneuroim.2019.01.010
• [Presentation] Increase of Mycobacterium avium subsp. Paratuberculosis (MAP) antibody in multiple sclerosis (2019)
  • Author(s): Isobe N, Hayashi F, Cossu D, Yokoyama K, Maimatijiang G, Nakamura Y, Matsushita T, Kira JI.
  • Organizer: 60th Annual Meeting of The Japanese Society of Neurology
• [Presentation] Disease-characteristic TCRs recognize CMV in Japanese MS with HLA-DRB1*04:05; a novel approach with GLIPH. (2019)
  • Author(s): Hayashi F, Isobe N, Glanville J, Matsushita T, Kira J.
  • Organizer: 60th Annual Meeting of The Japanese Society of Neurology
• [Presentation] Progressive multifocal leukoencephalopathy in the era of disease-modifying therapies. Genetic backgrounds of Japanese MS and JC virus antibody. (2019)
  • Author(s): Isobe N.
  • Organizer: 60th Annual Meeting of The Japanese Society of Neurology
• [Presentation] T cell receptor repertoire in a monozygotic triplet discordant for multiple Sclerosis. (2019)
  • Author(s): Isobe N, Hayashi F, Matsushita T, Okamoto K, Kira JI.
  • Organizer: 35th Congress of The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
  • Int'l Joint Research
• [Presentation] HLA-DRB1*04:05陽性MS患者におけるサイトメガロウイルス（CMV）関連T細胞受容体の同定． (2019)
  • Author(s): 林史恵、磯部紀子、Jacob Glanville、松下拓也、吉良潤一．
  • Organizer: 第31回日本神経免疫学会学術集会
• [Presentation] 表現型不一致の一卵性品胎における多発性硬化症関連Ｔ細胞受容体レパトア解析． (2019)
  • Author(s): 磯部紀子、林史恵、渡邉充、松下拓也、岡本幸市、吉良潤一．
  • Organizer: 第31回日本神経免疫学会学術集会
• [Presentation] Genetic approach for disease heterogeneity of multiple sclerosis: for the era of precision medicine. Perspectives on Personalized Medicine for Multiple Sclerosis. (2019)
  • Author(s): Isobe N.
  • Organizer: 12th Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS)
  • Int'l Joint Research
• [Presentation] Increase of EBV lytic infection in Japanese patients with multple sclerosis. (2019)
  • Author(s): Isobe N, Dilek HF, Sakoda A, Hayashi F, Watanabe M, Matsushita T, Kira JI.
  • Organizer: The 12th Congress of the PACTRIMS
  • Int'l Joint Research