Molecular evolutionary analysis of schizophrenia susceptibility genes.

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590360
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: Kyushu University
• Principal Investigator: SHIBATA Hiroki 九州大学, 生体防御医学研究所・ゲノム機能学分野 (80315093)
• Project Period (FY): 2009 – 2011
• Keywords: 進化医学 / 集団遺伝学 / 自然選択 / 統合失調症

Research Abstract

Schizophrenia has a relatively strong genetic background(λs=10). Because of the typically adolescent onset and the loss of sociality in patients, schizophrenia susceptibility alleles are expected to be selected out through generations. However, the prevalence is stably high at~ 1% in any of the populations surveyed. To explain the paradox, I hypothesized that the schizophrenia susceptibility alleles are maintained by the non-neutral process such as balancing selection. To test this hypothesis, I sequenced six schizophrenia susceptibility genes, BDNF, SLC18A1, COMT, DRD1, DRD2, DRD4 from 72 unrelated humans(24 Caucasians, 24 African Ameericans and 24 Japanese) and 24 unrelated chimpanzees as non-human controls. Using the variation data set, I examined neutrality by the summary statistics approach such as Tajima' s method. I identified a significant signal of balancing selection in the regions of coding SNPs in DRD2(rs6275, rs6277) and in COMT(rs4680). All of these SNPs a significant association has been frequently reported with schizophrenia. By coalescent simulation I dated the haplotypes in the selected regions in both genes to be> 1 MYA. I conclude that some of the schizophrenia susceptible alleles have been maintained by balancing selection of which the target may be the phenotypes related to schizophrenia as well as human brain functions.

Research Products

• [Journal Article] Crohn' s disease risk alleles on the NOD2 locus have been maintained by natural selection on standing variation (2012)
  • Author(s): Nakagome S, Mano S, Kozlowski L, Bujnicki JM, Shibata H, Fukumaki Y, Kidd JR, Kidd KK, Kawamura S, Oota H.
  • Journal Title: Mol Biol Evol Volume: 5
  • Peer Reviewed
• [Journal Article] Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family (2011)
  • Author(s): Miura S, Shibata H, Kida H, Noda K, Toyama T, Iwasaki N, Iwaki A, Ayabe M, Aizawa H, Taniwaki T, Fukumaki Y.
  • Journal Title: Neurogenetics Volume: 12(1) Pages: 25-31
  • Peer Reviewed
• [Journal Article] Positive association of phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia (2011)
  • Author(s): Deng X, Takaki H, Wang L, Kuroki T, Nakahara T, Hashimoto K, Ninomiya H, Arinami T, Inada T, Ujike H, Itokawa M, Tochigi M, Watanabe Y, Someya T, Kunugi H, Iwata N, Ozaki N, Shibata H, Fukumaki Y.
  • Journal Title: Am J Med Genet Neuropsychiatr Genet Volume: 156(7) Pages: 850-858
  • Peer Reviewed
• [Journal Article] The identification and functional implications of human-specific" fixed" amino acid substitutions in the glutamate receptor family (2009)
  • Author(s): Goto H, Watanabe K, Araragi N, Kageyama R, Tanaka K, Kuroki Y, Toyoda A, Hattori M, Sakaki Y, Fujiyama A, Fukumaki Y, Shibata H.
  • Journal Title: BMC Evol Biol Volume: 9 Pages: 224
  • Peer Reviewed
• [Presentation] Non-neutral evolution observed in schizophrenia susceptibility genes.(ワークショップ) (2011)
  • Author(s): Shibata S.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] Population specific susceptibility to Crohn' s disease and signals of natural selection on standing variation (2011)
  • Author(s): Nakagome S, Mano S, Kozlowski L, Bujnicki JM, Shibata H, Fukumaki Y, Kidd JR, Kidd KK, Kawamura S, Oota H.
  • Organizer: 12th International Congress of Human Genetics/61st Annual Meeting of The American Society of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20111011-15
• [Presentation] Exome sequencing approach to identify the responsible variant for a novel type of hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities found in a Japanese descent (2011)
  • Author(s): Shibata H, Miura S, Kida H, Noda K, Kaku Y, Iwaki A, Ayabe M, Taniwaki T, Fukumaki Y.
  • Organizer: 12th International Congress of Human Genetics/61st Annual Meeting of The American Society of Human Genetics
  • Place of Presentation: Montreal, Canada
  • Year and Date: 20111011-15
• [Presentation] 統合失調症関連候補遺伝子としてのPCP応答遺伝子探索と関連解析 (2010)
  • Author(s): 〓湘東、柴田弘紀、高木宏美、王麗香、黒木俊秀、中原辰雄、橋本喜次郎、岩田仲生、尾崎紀夫、有波忠雄、服巻保幸.
  • Organizer: 日本人類遺伝学会第55回大会
  • Place of Presentation: さいたま
  • Year and Date: 20101027-30
• [Presentation] 統合失調症感受性遺伝子COMTに見出される中立進化からの逸脱 (2010)
  • Author(s): 柴田弘紀、内田麻衣子、後藤大輝、間野修平、竹中修、服巻保幸.
  • Organizer: 日本人類遺伝学会第55回大会
  • Place of Presentation: さいたま
  • Year and Date: 20101027-30
• [Presentation] 統合失調症感受性遺伝子COMTに見出される中立進化からの逸脱 (2010)
  • Author(s): 柴田弘紀、内田麻衣子、後藤大輝、間野修平、竹中修、服巻保幸.
  • Organizer: 第82回日本遺伝学会大会
  • Place of Presentation: 札幌
  • Year and Date: 20100920-23
• [Presentation] 統合失調症の原因を進化的手法で探る.天才とナントカは紙一重か?.(ワークショップ) (2010)
  • Author(s): 柴田弘紀.
  • Organizer: 第12回日本進化学会大会
  • Place of Presentation: 東京
  • Year and Date: 20100802-05
• [Presentation] Molecular evolutionary study of the ionotropic glutamate-receptor gene family as schizophrenia susceptibility genes : human-specific balancing selection in GRIN2B upstream region. International Symposium on Biodiversity Sciences (2010)
  • Author(s): Shibata H, Tanaka K, Watanabe K, Goto H, Mano S, Takenaka O, Fukumaki Y.
  • Organizer: Genome, Evolution and Environment
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 20100731-0803
• [Presentation] マイクロサテライトマーカーを用いた統合失調症のゲノムワイド関連解析 (2010)
  • Author(s): 服巻保幸、山本健、岡晃、猪子英俊、有波忠雄、岩田仲生、尾崎紀夫、柴田弘紀.
  • Organizer: 第5回日本統合失調症学会
  • Place of Presentation: 福岡
  • Year and Date: 20100326-27
• [Presentation] 統合失調症感受性遺伝子としてのグルタミン酸受容体遺伝子群の集団遺伝学手法による自然選択の検出 (2010)
  • Author(s): 柴田弘紀、田中邦佳、渡邉和典、後藤大輝、間野修平、竹中修、服巻保幸.
  • Organizer: 第5回日本統合失調症学会
  • Place of Presentation: 福岡
  • Year and Date: 20100326-27
• [Presentation] Resequencing of dopamine receptor genes DRD1 and DRD2 as schizophrenia susceptibility genes revealed non-neutral process possibly associated with schizophrenia (2010)
  • Author(s): Liang Y, Fukumaki Y, Shibata H.
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-07-10
• [Presentation] Resequencing of the catechol-O-methyltransferase gene, COMT revealed non-neutral processes associated with schizophrenia (2010)
  • Author(s): Shibata H, Uchida M, Goto H, Mano S, Takenaka O, Fukumaki Y.
  • Organizer: 60th Annual Meeting of The American Society of Human Genetics, Washington
  • Place of Presentation: DC
  • Year and Date: 2010-02-06
• [Presentation] Molecular evolutionary study of the COMT gene as a schizophrenia susceptibility gene (2009)
  • Author(s): Uchida M, Fukumaki Y, Shibata S.
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20091209-12
• [Presentation] Molecular evolutionary study of the ionotropic glutamate-receptor gene family as schizophrenia susceptibility genes : human-specific balancing selection in the GRIN2B upstream region (2009)
  • Author(s): Shibata H, Watanabe K, Tanaka K, Goto H, Mano S, Takenaka O, Fukumaki Y.
  • Organizer: 59th Annual Meeting of The American Society of Human Genetics, Honolulu
  • Place of Presentation: HI
  • Year and Date: 20091021-24
• [Presentation] Genome-wide association study of schizophrenia using STR markers (2009)
  • Author(s): Fukumaki Y, Yamamoto K, Sun Z, Oka A, Inoko H, Arinami T, Iwata N, Ozaki N, Shibata H.
  • Organizer: 9th Annual Meeting of The American Society of Human Genetics, Honolulu
  • Year and Date: 20091021-24
• [Presentation] 統合失調症のSTRマーカーによるゲノムワイド関連解析￥ (2009)
  • Author(s): 服巻保幸、山本健、孫竹、岡晃、猪子英俊、有波忠雄、岩田仲生、尾崎紀夫、柴田弘紀.
  • Organizer: 日本人類遺伝学会第54回大会
  • Place of Presentation: 東京
  • Year and Date: 20090923-26
• [Presentation] 高次脳機能関連遺伝子群の分子進化学的解析:代謝調節型グルタミン酸受容体遺伝子群における自然選択の検出 (2009)
  • Author(s): 柴田弘紀、森田彩、後藤大輝、間野修平、竹中修、服巻保幸.
  • Organizer: 日本人類遺伝学会第54回大会
  • Place of Presentation: 東京
  • Year and Date: 20090923-26
• [Presentation] 高次脳機能関連遺伝子群の分子進化学的解析:代謝調節型グルタミン酸受容体遺伝子群における自然選択の検出 (2009)
  • Author(s): 柴田弘紀、森田彩、後藤大輝、間野修平、竹中修、服巻保幸.
  • Organizer: 第81回日本遺伝学会大会
  • Place of Presentation: 松本
  • Year and Date: 20090916-18
• [Presentation] Molecular Evolutionary Study Of The Ionotropic Glutamate-Receptor Gene Family As Schizophrenia Susceptibility Genes : Human-Specific Balancing Selection In GRIN2B Upstream Region (2009)
  • Author(s): Shibata H, Tanaka K, Watanabe K, Goto H, Mano S, Takenaka O, Fukumaki Y.
  • Organizer: The 8th International Workshop on Advanced Genomics : Expansion of Genome Science, Tokyo
  • Place of Presentation: Japan
  • Year and Date: 20090616-18
• [Presentation] 高次脳機能関連遺伝子群の分子進化学的解析:代謝調節型グルタミン酸受容体遺伝子群における自然選択の検出 (2009)
  • Author(s): 柴田弘紀、森田彩、後藤大輝、間野修平、竹中修、服巻保幸.
  • Organizer: 第11回日本進化学会大会
  • Place of Presentation: 札幌
  • Year and Date: 2009-02-04
• [Book] ヒトは病気とともに進化した(仮題) (2012)
  • Author(s): 柴田弘紀.
  • Publisher: 勁草書房