Identification of susceptibility genes for functional psychoses by whole genome scan

全基因组扫描鉴定功能性精神病易感基因

• 批准号: 12307020
• 负责人: YOSHIKAWA Takeo
• 金额: $ 22.84万
• 依托单位: RIKEN
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12307020/
• 关键词: schizophrenia; pedigree; genome scan; family-based association; chromosome 11; chromosome 18; choline knase; C18orf1; ETDT; ハプロタイプ; C18orf1; SNP; マイクロサテライトマーカー; 内因性精神病; 精神分裂病; 感情病; 全ゲノムassociation study; IMPA2遺伝子; 学習性無力ラット; gene chip

Family-based linkage disequilibrium (LD) mapping has been suggested as a powerful and practical alternative to linkage analysis. We have performed a genome-wide LD survey of susceptibility loci for schizophrenia in a Japanese population. We first typed 119 schizophrenic pedigrees (357 individuals) with 444 microsatellite markers, and analyzed the data using the pedigree disequilibrium test. This analysis revealed 14 markers that showed significant transmission distortion. To corroborate these findings, we changed our statistical methods to the extended transmission disequilibrium test (ETDT) , using 80 independent complete trios (a schizophrenic offspring and their parents), 68 of which were derived from the initial pedigrees and 12 newly recruited trios. ETDT supported two markers for continued association, D11S987 on 11q13.3 (P=0.00009) and D16S423 on 16p13.3 (P=0.002). We scrutinized the most significant genomic locus on 11q11-13 by adding 26 new markers for analysis. Results of three-marker haplotype analysis in the region showed evidence of association with schizophrenia (most significant haplotype P=0.0005, global P=0.022). Although the present study may have missed other potential genomic intervals because of the sparse mapping density, we hope that it has identified promising anchor points for further studies to identify risk-conferring genes in Japanese schizophrenia.

基于家系的连锁不平衡(LD)作图已被认为是一种强大而实用的连锁分析替代方法。我们对日本人群中精神分裂症的易感基因进行了全基因组LD调查。我们首先用444个微卫星标记对119个精神分裂症家系(357个个体)进行分型，并用家系不平衡检验对数据进行分析。这项分析揭示了14个标记，它们显示出显著的传递失真。为了证实这些发现，我们将我们的统计方法改为扩展传递不平衡检验(ETDT)，使用了80个独立的完整三联体(一个精神分裂症患者的后代及其父母)，其中68个来自最初的家系，12个新招募的三联体。Etdt支持两个标记继续关联，D11S987位于11q13.3(P=0.00009)，D16S423位于16p13.3(P=0.002)。通过添加26个新的标记进行分析，我们仔细研究了11q11-13上最重要的基因组座位。该地区的三标记单倍型分析结果显示与精神分裂症有关(最显著的单倍型P=0.0005，全球P=0.022)。尽管由于图谱密度的稀疏，本研究可能遗漏了其他潜在的基因组区间，但我们希望它已经为进一步研究确定日本精神分裂症的风险相关基因找到了有希望的锚点。

项目成果

菊池美香 他: "融解曲線分析を用いた新しい遺伝子タイピング法およびIMPA2遺伝子解析への応用"脳と精神の医学12,63-71,2001. 12. 63-71 (2001)

Mika Kikuchi 等人：“使用熔解曲线分析的新基因分型方法及其在 IMPA2 基因分析中的应用” Brain and Psychiatric Medicine 12, 63-71, 2001. 12. 63-71 (2001)

Yoshikawa T. et al.: "Genomic Structure and novel variants of myo-inositol monophosphatase 2 (MPA2)"Molecular Psychiatry. 5. 165-171 (2000)

Yoshikawa T. 等人：“肌醇单磷酸酶 2 (MPA2) 的基因组结构和新变体”分子精神病学。

Ohtsuki T. et al.: "WFS1 gene mutation search in depressive patients : Detection of 5 missense polymorphisms but no association with depression or bipolar affective disorder"Journal of Affective Disorders. 58. 11-17 (2000)

Ohtsuki T.等人：“抑郁症患者中的WFS1基因突变搜索：检测到5个错义多态性，但与抑郁症或双相情感障碍无关”情感障碍杂志。

Kurumaj i A.: "An association study of polymorphism in the first intron of the tyrosine hydroxylase gene with affective disorders"Brain Science and Mental Disorders. 11. 57-61 (2000)

Kurumaj i A.：“酪氨酸羟化酶基因第一个内含子多态性与情感障碍的关联研究”《脑科学与精神障碍》。

Toyota, T. et al.: "Karyotpre analysis of 161 unrelated schizophrenics : no increased rates of X chromosome mosaicism or inv(9), using ethnically matched and age-stratified controls"Schizophrenia Research. 52. 171-179 (2001)

Toyota, T. 等人：“对 161 名不相关的精神分裂症患者进行 Karyotpre 分析：使用种族匹配和年龄分层对照，X 染色体嵌合或 inv(9) 的比率没有增加”精神分裂症研究。