{"created":"2023-06-19T07:19:16.977536+00:00","id":5300,"links":{},"metadata":{"_buckets":{"deposit":"23d4f8d5-d912-485f-889b-6e5a6e135dfc"},"_deposit":{"created_by":4,"id":"5300","owners":[4],"pid":{"revision_id":0,"type":"depid","value":"5300"},"status":"published"},"_oai":{"id":"oai:az.repo.nii.ac.jp:00005300","sets":["370:197:377"]},"author_link":["22937","22936"],"item_10006_date_granted_11":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"2018-03-15"}]},"item_10006_degree_grantor_9":{"attribute_name":"学位授与機関","attribute_value_mlt":[{"subitem_degreegrantor":[{"subitem_degreegrantor_name":"麻布大学"}],"subitem_degreegrantor_identifier":[{"subitem_degreegrantor_identifier_name":"32701","subitem_degreegrantor_identifier_scheme":"kakenhi"}]}]},"item_10006_degree_name_8":{"attribute_name":"学位名","attribute_value_mlt":[{"subitem_degreename":"博士(学術)"}]},"item_10006_description_22":{"attribute_name":"Abstract","attribute_value_mlt":[{"subitem_description":"　The objective of this research was to elucidate the genetic factors involved in individual differences in alcohol dependence vulnerability and related personality traits by analyzing single nucleotide polymorphisms (SNPs) of two genes, thereby facilitating the development of individually tailored medicines.\n\n　Alcohol dependence is a form of drug addiction that involves loss of control as to alcohol consumption, and is hereditary. It is suggested that alcohol dependence is due to an abnormality in the brain reward system relating to anxiety and pleasant emotions. The autism susceptibility candidate 2 (AUTS2) which plays an important role in the development of the cranial nervous system, is broadly involved in various psychiatric disorders including autism. Recent studies reported that the rs6943555 polymorphism in the AUTS2 gene (AUTS2) is related to heroin dependence, and this polymorphism also affects individual alcohol consumption as shown by a genome-wide association study meta-analysis. The N-methyl-D-aspartate (NMDA) receptor, which is a type of glutamate receptor, is one of the primary targets of ethanol in the brain. It has been reported that the NMDA receptor subunit 2B (GluN2B) of the NMDA receptor increases its expression in response to chronic ethanol exposure. In addition, a case-control study in another population revealed that a polymorphism and several haplotypes of the GluN2B gene (GRIN2B) are associated with alcohol dependence. From the above points, a contribution to the brain reward system by both genes is predicted. In this study, to elucidate their effects on individual differences in alcohol dependence vulnerability, the author focused on nine SNPs, including functional polymorphisms in AUTS2 and GRIN2B, and compared the difference in frequencies of these polymorphisms between patients with alcohol dependence and healthy control subjects living in a Japanese provincial prefecture.\n　The subjects in this study consisted of 64 patients (male: 50, female: 7, not available: 7; mean age ± SD: 57.34 ± 10.18 years) with a diagnosis of alcohol dependence according to the DSM-IV criteria, and 75 unrelated healthy people (male: 23, female: 52; mean age ± SD: 35.36 ± 9.06 years). Blood samples were collected from the subjects, all of whom provided written informed consent for genetic studies. All of the patients and control subjects lived in Yamagata prefecture in Japan. The AUTS2 (rs6943555 and rs9886351) and GRIN2B (rs3764028, rs1019385, rs7301328, rs1806201, rs1805247, rs890 and rs1805502) polymorphisms were genotyped by the polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) method.\n　In genotype and allele frequency analysis, there were no significant differences in the genotype or allele frequencies of AUTS2 polymorphisms rs6943555 and rs9886351 between alcohol-dependent and control subjects. On the other hand, haplotype analysis indicated that the frequency of the A-A haplotype consisting of the polymorphisms rs6943555 and rs9886351 was significantly different between the alcohol-dependent and control subjects (p = 0.019). The patient group showed a significantly higher frequency of the A-A haplotype as compared with the control group. Besides, there were significant differences in the genotype (p = 0.019) and allele (p = 0.044) frequencies of GRIN2B polymorphisms rs1805247 and rs1805502 (complete linkage disequilibrium in the analyzed population) between the alcohol-dependent and control subjects, and the proportion of C allele carriers of these polymorphisms was significantly higher in the patient group than in the control group (p = 0.007). Haplotype analysis indicated a marginally significant association between the C-C-C haplotype in the GRIN2B haplotype block (rs1806201-rs1805247-rs1805502) and alcohol dependence (p = 0.054). Other GRIN2B polymorphisms and haplotypes were not significantly associated with alcohol dependence.\n　These results suggested that the polymorphisms and haplotypes of the AUTS2 and GRIN2B might be one of the risk factors for alcohol dependence in a Japanese population. Alcohol drinking behavior is influenced by different environmental factors in various countries and races. Therefore, these findings in the first study on a Japanese population are important, and they are expected to help elucidate the pathology of alcohol dependence, and to lead to early prevention and treatment based on features of individuals’ genetic backgrounds. In order to obtain more clinically meaningful findings, further studies with more subjects considering possible biases are needed to confirm the reproducibility of the results of this study.\n\n　Personality traits are influenced not only by environmental factors but also by genetic ones. Some genes involved in the characterization of personality traits have aspects affecting various behaviors, and associations with gene polymorphisms that contribute to some disorders such as mood disorders, schizophrenia, and drug addiction have been reported. It has been suggested that the AUTS2 and GRIN2B affect various human mental functions and behaviors, and both genes may be involved in personality traits. To date, a study on the relationship between the AUTS2 polymorphisms and personality traits has not yet been reported, and there are few studies that have reported the relationship between the GRIN2B polymorphisms and personality traits. In this study, the author focused on the AUTS2 and GRIN2B polymorphisms that have been shown to affect human mental function and behavior (including SNPs found to be associated with alcohol dependence in the above-mentioned study), and investigated whether these polymorphisms are related to the individual differences in personality traits.\n　For analysis of association with AUTS2 polymorphisms, the participants comprised 190 young people (male: 51, female: 139; mean age ± SD: 20.46 ± 1.15 years), and personality traits were assessed using the Temperament and Character Inventory (TCI). In order to exclude the influence of subjects with depressive symptoms on the results, the Patient Health Questionnaire-9 (PHQ-9) was also performed. For analysis of association with GRIN2B polymorphisms, the participants comprised 248 young people (male: 63, female: 185; mean age ± SD: 19.55 ± 1.21 years), and personality traits were assessed using the NEO-Five Factor Inventory (NEO-FFI) and State-Trait Anxiety Inventory (STAI). The AUTS2 (rs6943555 and rs9886351) and GRIN2B (rs7301328, rs1806201, rs1805247 and rs1805502) polymorphisms were genotyped by means of the PCR-RFLP method.\n　In all subjects, two-way analysis of variance showed that there was a significant main effect of the AUTS2 polymorphism rs6943555 genotype on reward dependence (p = 0.038) and cooperativeness (p = 0.031) of the TCI dimensions, although the association was lost on Bonferroni correction. In addition, no significant association was found between AUTS2 polymorphisms and haplotypes and TCI dimensions when subjects with moderate or higher depressive symptoms according to the PHQ-9 were excluded. Similarly, two-way analysis of variance showed no significant effects of the GRIN2B polymorphisms on the NEO-FFI and STAI dimensions. In female subjects, the C-T-T haplotype in the GRIN2B haplotype block (rs1806201-rs1805247-rs1805502) was significantly associated with extraversion (p = 0.044) of the NEO-FFI dimensions, although the association was lost on Bonferroni correction.\n　In summary, this study was unable to detect a significant association between the selected AUTS2 and GRIN2B polymorphisms and personality traits. Several studies have revealed that the glutamatergic neurotransmission system plays some role in the characterization of human behavior and personality traits. It is reported that AUTS2 is expressed in glutamatergic neurons, and this gene may be affecting personality traits by interaction with glutamate-related genes such as GRIN2B. Further studies using other personality questionnaires with different characteristics are therefore needed to clarify the relationship between both genes and personality traits, and it would be meaningful also to analyze the effect of interactions between the AUTS2 and GRIN2B polymorphisms.\n","subitem_description_type":"Other"}]},"item_10006_description_7":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"本研究では、テーラーメイド医療の一助となることを目的とし、アルコール依存脆弱性や人格特性の個人差にかかわる遺伝的要因の解明のため、遺伝子多型解析による検討を行った。その概要は以下の通りである。\n　アルコール依存症はアルコール消費に対する制御喪失を伴う薬物依存の一形態であり、その発症脆弱性には遺伝的関与が認められる。これまでの研究から、不安や快情動に関わる脳内報酬システムの異常がアルコール依存形成に繋がることが指摘されている。脳神経系の発達に重要な役割を担うとされるautism susceptibility candidate 2（AUTS2）は自閉症をはじめとする種々の精神疾患に広く関与することが知られている。最近の研究では、AUTS2遺伝子（AUTS2）上に存在するrs6943555多型が薬物依存症の一種であるヘロイン依存に関与することが報告され、さらにゲノムワイド関連解析のメタ解析において同多型が個人のアルコール消費量にも影響を与えることが明らかとなった。また、グルタミン酸受容体の一種であるN-methyl-D-aspartate（NMDA）受容体は脳内におけるエタノールの主要な作用部位の一つとされ、そのサブユニットとして知られるNMDA受容体サブユニット2B（GluN2B）は慢性エタノール曝露によりその発現が増加することが報告されている。さらに、他国における研究ではGluN2B遺伝子（GRIN2B）の多型やハプロタイプがアルコール依存症に関与することが確認された。以上の点から、両遺伝子の脳内報酬システムへの寄与が疑われる。本研究では、AUTS2およびGRIN2B上に存在する機能性多型を含む9つの一塩基多型（Single Nucleotide Polymorphisms: SNPs）に着目し、それらの頻度を日本の一地域におけるアルコール依存症患者群と同一地域の健常者群間で比較解析することで、アルコール依存脆弱性の個人差に対する影響について検討した。\n　対象はDSM-IVの診断基準においてアルコール依存症と診断されたアルコール依存症患者64人（男性50人、女性7人、不明7人、平均年齢57.34 ± 10.18歳）およびアルコール依存の経歴のない健常者75人（男性23人、女性52人、平均年齢35.36 ± 9.06歳）とし、対象者から同意を得た上で採血を行った。すべての対象者は山形県在住である。また、解析対象となるAUTS2（rs6943555、rs9886351）およびGRIN2B（rs3764028、rs1019385、rs7301328、rs1806201、rs1805247、rs890、rs1805502）多型の遺伝子型はpolymerase chain reaction（PCR）- restriction fragment length polymorphism（RFLP）法により決定した。\n　比較解析の結果、アルコール依存症患者群と健常者群の間でAUTS2多型のrs6943555およびrs9886351の遺伝子型と対立遺伝子の頻度に有意な差異は認められなかった。一方、ハプロタイプ解析の結果、アルコール依存症患者群と健常者群の間でrs6943555およびrs9886351からなるA-Aハプロタイプの頻度に有意な差異を認め（p = 0.019）、健常者群に比べ患者群において高頻度に検出された。また、本解析集団において完全連鎖不平衡の関係にあったGRIN2B多型のrs1805247およびrs1805502の遺伝子型（p = 0.019）と対立遺伝子（p = 0.044）の頻度にアルコール依存症患者群と健常者群の間で有意な差異を認め、C対立遺伝子保有者の割合が健常者群に比べ患者群において有意に高かった（p = 0.007）。ハプロタイプ解析の結果、本解析集団において検出されたGRIN2Bハプロタイプブロック（rs1806201-rs1805247-rs1805502）のC-C-Cハプロタイプとアルコール依存症との間に関連傾向を認めた（p = 0.054）。その他のGRIN2Bの多型やハプロタイプについては、アルコール依存症との関連は認められなかった。\n　以上より、AUTS2およびGRIN2Bの多型やハプロタイプがアルコール依存症発症の危険因子の一つとして推測され、それらの分子生物学的機能により脳内報酬システムに少なからず影響を与える可能性が示唆された。飲酒行動は様々な国や人種で異なる環境要因の影響を受けるため、日本人を対象とした初めての研究で得た本知見は重要であり、アルコール依存症の病態解明、早期の予防や治療に繋がることが期待される。今後はさらなるエビデンスの構築を目指し、大規模な他集団において結果の再現性を確認することで、より臨床的意義の高い知見が得られるものと示唆される。\n　人格特性の形成には環境的要因だけでなく遺伝的要因も関与している。人格特性の形成にかかわる遺伝子はヒトの行動に広く影響を与え、その背景には気分障害や統合失調症、薬物依存症などの発症に寄与する遺伝子多型との関連が報告されている。これまでにAUTS2やGRIN2Bがヒトの様々な精神機能や行動に影響を与えることが示唆されており、人格特性に影響を与える可能性は否定できない。AUTS2多型と人格特性との関連を検討した研究はこれまでに行われておらず、GRIN2B多型との関連についての報告も少ない。本研究では、前述でアルコール依存症との関連を認めたSNPsを含む、ヒトの精神機能や行動への影響が報告されているAUTS2およびGRIN2B多型に焦点を当て、それらの多型が人格特性の形成に関与する可能性について検討した。\n　AUTS2多型を解析対象とした研究では、同意を得た若年者190人（男性51人、女性139人、平均年齢20.46 ± 1.15歳）を対象とし、人格特性の評価には自己記入式人格検査のTemperament and Character Inventory（TCI）を用いた。また、抑うつ症状を有する対象者による結果への影響を除外するために抑うつ評価尺度のPatient Health Questionnaire-9（PHQ-9）を実施した。GRIN2B多型を解析対象とした研究では、同意を得た若年者248人（男性63人、女性185人、平均年齢19.55 ± 1.21歳）を対象とし、人格特性の評価には自己記入式人格検査のNEO-Five Factor Inventory（NEO-FFI）とState-Trait Anxiety Inventory（STAI）を用いた。AUTS2（rs6943555、rs9886351）およびGRIN2B（rs7301328、rs1806201、rs1805247、rs1805502）多型の遺伝子型はPCR-RFLP法により決定した。\n　二元配置分散分析の結果、対象者全員においてAUTS2多型rs6943555のTCI気質尺度の報酬依存（p = 0.038）と性格尺度の協調（p = 0.031）に対する有意な主効果を検出したが、Bonferroni補正によりその関連性は消失した。さらに、PHQ-9により中等度以上の抑うつ症状を有する対象者を除外して解析を行ったが、AUTS2多型やハプロタイプとTCI尺度との有意な関連は認められなかった。同様に、二元配置分散分析の結果、GRIN2B多型のNEO-FFIおよびSTAI尺度に対する有意な効果は検出されなかった。また、女性において本解析集団で検出されたGRIN2Bハプロタイプブロック（rs1806201-rs1805247-rs1805502）のC-T-TハプロタイプとNEO-FFI尺度の外向性（p = 0.044）との間に有意な関連を認めたが、Bonferroni補正によりその関連性は消失した。\n　以上より、本研究で解析対象としたAUTS2およびGRIN2B多型と人格特性との有意な関連を検出することはできなかった。グルタミン酸作動性神経伝達システムはヒトの行動や人格特性に対し、いくつかの役割を担うことが示唆されている。AUTS2はグルタミン酸作動性ニューロンに発現していることが報告されており、同遺伝子がGRIN2Bなどのグルタミン酸関連遺伝子との相互作用により人格特性の形成に影響を与えている可能性も考えられる。今後、人格特性との関連を解明するため、異なる特徴を有する他の人格検査を用いて検討することが必要であり、両遺伝子多型の相互作用についての解析も意義があると考える。\n","subitem_description_type":"Abstract"}]},"item_10006_dissertation_number_12":{"attribute_name":"学位授与番号","attribute_value_mlt":[{"subitem_dissertationnumber":"甲第32号"}]},"item_10006_textarea_23":{"attribute_name":"Rights","attribute_value_mlt":[{"subitem_textarea_value":"本論文の一部は以下のとおり公表されている。(Part of this dissertation has been published as follows.) \n・Narita, S., Nagahori, K., Nishizawa, D., Yoshihara, E., Kawai, A., Ikeda, K., Iwahashi, K.: Association between AUTS2 haplotypes and alcohol dependence in a Japanese population. Acta Neuropsychiatrica, 28: 214-220, 2016. DOI: 10.1017/neu.2015.70\n・Narita, S., Yoshihara, E., Nishizawa, D., Kawai, A., Ikeda, K., Iwahashi, K.:\nAssociation between N-methyl-D-aspartate receptor subunit 2B gene polymorphisms and alcohol dependence in a Japanese population. Nihon Arukoru Yakubutsu Igakkai Zasshi, 52: 156-167, 2017.\n・Narita, S., Ikeda, K., Nishizawa, D., Yoshihara, E., Numajiri, M., Onozawa, Y., Ohtani, N., Iwahashi, K.: No association between the polymorphism rs6943555 in the AUTS2 gene and personality traits in Japanese university students. Psychiatry Investigation, 14: 681-686, 2017. DOI: 10.4306/pi.2017.14.5.681\n・Narita, S., Onozawa, Y., Yoshihara, E., Nishizawa, D., Numajiri, M., Ikeda, K., Iwahashi, K.: Association between N-methyl-D-aspartate receptor subunit 2B gene polymorphisms and personality traits in a young Japanese population. East Asian\nArchives of Psychiatry, 28: 45-52, 2018. DOI: 10.12809/eaap181712\n[Permission to reproduce this article ({give full reference}) in this dissertation has been granted by the journal. © 2017-18 Hong Kong College of Psychiatrists]\n"}]},"item_10006_version_type_18":{"attribute_name":"著者版フラグ","attribute_value_mlt":[{"subitem_version_resource":"http://purl.org/coar/version/c_970fb48d4fbd8a85","subitem_version_type":"VoR"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"open access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_abf2"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"成田, 心"}],"nameIdentifiers":[{"nameIdentifier":"22936","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Narita, Shin","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"22937","nameIdentifierScheme":"WEKO"}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2018-09-20"}],"displaytype":"detail","filename":"diss_de_kou0032.pdf","filesize":[{"value":"2.6 MB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"diss_de_kou0032","url":"https://az.repo.nii.ac.jp/record/5300/files/diss_de_kou0032.pdf"},"version_id":"19dbe953-744a-4184-9275-225afb32a437"},{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2018-03-28"}],"displaytype":"detail","filename":"diss_de_kou0032_jab&rev.pdf","filesize":[{"value":"178.6 kB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"diss_de_kou0032_jab&rev.pdf","url":"https://az.repo.nii.ac.jp/record/5300/files/diss_de_kou0032_jab&rev.pdf"},"version_id":"a919fcfc-9327-44d2-b738-6059042186f0"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"doctoral thesis","resourceuri":"http://purl.org/coar/resource_type/c_db06"}]},"item_title":"アルコール依存脆弱性や人格特性の個人差に対する autism susceptibility candidate 2 および N-methyl-D-aspartate receptor subunit 2B 遺伝子多型の寄与","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"アルコール依存脆弱性や人格特性の個人差に対する autism susceptibility candidate 2 および N-methyl-D-aspartate receptor subunit 2B 遺伝子多型の寄与"},{"subitem_title":"The contribution of autism susceptibility candidate 2 and N-methyl-D- aspartate receptor subunit 2B gene polymorphisms to individual differences in alcohol dependence vulnerability and personality traits","subitem_title_language":"en"}]},"item_type_id":"10006","owner":"4","path":["377"],"pubdate":{"attribute_name":"公開日","attribute_value":"2018-03-28"},"publish_date":"2018-03-28","publish_status":"0","recid":"5300","relation_version_is_last":true,"title":["アルコール依存脆弱性や人格特性の個人差に対する autism susceptibility candidate 2 および N-methyl-D-aspartate receptor subunit 2B 遺伝子多型の寄与"],"weko_creator_id":"4","weko_shared_id":4},"updated":"2023-06-19T07:42:37.230697+00:00"}