Testing the DISC1 pathway for functional genetic variation and epistasis in major

测试主要功能遗传变异和上位性的 DISC1 通路

• 批准号: 8881325
• 负责人: William Richard McCombie
• 金额: $ 61.55万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881325
• 关键词: Age of Onset; Algorithms; American; Amino Acid Substitution; Biological; Bipolar Disorder; Blood specimen; Brain; Cognition; Complex; Development; Diagnosis; Disease; Drug Targeting; Epigenetic Process; Equilibrium; Family; Gene Expression; Genes; Genetic; Genetic Epistasis; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Goals; Health; Individual; Link; Major Depressive Disorder; Measures; Mental Depression; Mental Health; Mental disorders; Methylation; Minor; Moods; Mutation; National Institute of Mental Health; Nature; Pathway interactions; Patients; Pattern; Phase; Phenotype; Proteins; Psychiatric Diagnosis; Public Health; Recurrence; Research Priority; Risk; Role; Sample Size; Sampling; Scaffolding Protein; Scanning; Schizophrenia; Signal Transduction; Spectrum Analysis; Testing; Ursidae Family; Variant; case control; genetic analysis; genetic variant; genome sequencing; genome wide association study; genome-wide; member; neurodevelopment; novel; risk variant; targeted sequencing

DESCRIPTION (provided by applicant): Major depression is a serious psychiatric disorder impacting the lives of millions of Americans. The gene DISC1 has been linked to this disorder by translocation in a single Scottish family as well as being supported by functional analyses of the gene prominent in neural development. We propose to carry out whole genome sequencing on 40 members of the original translocation family to identify possible variants that modify the effec of the translocation on phenotype as well as examine epigenetic differences in those that bear the translocation. We will also carry out genetic analyses by both genotyping and targeted sequencing to look for genetic differences in DISC1 and its core pathway genes in a total of nearly 10,000 people. Lastly, we will examine blood samples from some of those individuals with variants in the core pathway to determine if these variants change gene expression.

描述（由申请人提供）：重度抑郁症是一种严重的精神疾病，影响着数百万美国人的生活。DISC1基因在一个苏格兰家庭中通过易位与这种疾病有关，并且得到了神经发育中突出基因的功能分析的支持。我们建议对原始易位家族的40个成员进行全基因组测序，以确定可能的变体，这些变体修饰易位对表型的影响，并检查携带易位的表观遗传差异。我们还将通过基因分型和靶向测序进行遗传分析，以寻找DISC1及其核心途径基因的遗传差异，共近10，000人。最后，我们将检查一些在核心途径中具有变异的个体的血液样本，以确定这些变异是否会改变基因表达。

项目成果

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia.

• DOI: 10.1038/mp.2017.115
• 发表时间: 2018-05
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Teng S;Thomson PA;McCarthy S;Kramer M;Muller S;Lihm J;Morris S;Soares DC;Hennah W;Harris S;Camargo LM;Malkov V;McIntosh AM;Millar JK;Blackwood DH;Evans KL;Deary IJ;Porteous DJ;McCombie WR
• 通讯作者: McCombie WR

SuRFing the genomics wave: an R package for prioritising SNPs by functionality.

• DOI: 10.1186/s13073-014-0079-1
• 发表时间: 2014
• 期刊: Genome medicine
• 影响因子: 12.3
• 作者: Ryan NM;Morris SW;Porteous DJ;Taylor MS;Evans KL
• 通讯作者: Evans KL

DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder.

• DOI: 10.1186/s13148-016-0171-z
• 发表时间: 2016
• 期刊: Clinical epigenetics
• 影响因子: 5.7
• 作者: Walker RM;Christoforou AN;McCartney DL;Morris SW;Kennedy NA;Morten P;Anderson SM;Torrance HS;Macdonald A;Sussmann JE;Whalley HC;Blackwood DH;McIntosh AM;Porteous DJ;Evans KL
• 通讯作者: Evans KL

Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder.

• DOI: 10.1016/j.jpsychires.2015.01.006
• 发表时间: 2015-03
• 期刊: JOURNAL OF PSYCHIATRIC RESEARCH
• 影响因子: 4.8
• 作者: Walker, Rosie May;Rybka, Joanna;Anderson, Susan Maguire;Torrance, Helen Scott;Boxall, Ruth;Sussmann, Jessika Elizabeth;Porteous, David John;McIntosh, Andrew Mark;Evans, Kathryn Louise
• 通讯作者: Evans, Kathryn Louise

Preliminary assessment of pre-morbid DNA methylation in individuals at high genetic risk of mood disorders.

情绪障碍高遗传风险个体病前 DNA 甲基化的初步评估。

• DOI: 10.1111/bdi.12415
• 发表时间: 2016
• 期刊: Bipolar disorders
• 影响因子: 5.4
• 作者: Walker,RosieMay;Sussmann,JessikaElizabeth;Whalley,HeatherClare;Ryan,NiamhMargaret;Porteous,DavidJohn;McIntosh,AndrewMark;Evans,KathrynLouise
• 通讯作者: Evans,KathrynLouise