精神病生物型的遗传分析:共同祖先调整的多基因风险和独特的基因组关联

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Psychiatry Pub Date : 2024-12-21 DOI:10.1038/s41380-024-02876-z
Cuihua Xia, Ney Alliey-Rodriguez, Carol A. Tamminga, Matcheri S. Keshavan, Godfrey D. Pearlson, Sarah K. Keedy, Brett Clementz, Jennifer E. McDowell, David Parker, Rebekka Lencer, S. Kristian Hill, Jeffrey R. Bishop, Elena I. Ivleva, Cindy Wen, Rujia Dai, Chao Chen, Chunyu Liu, Elliot S. Gershon
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引用次数: 0

摘要

双相精神分裂症中间表型网络(B-SNIP)基于多祖先样本的神经生物学测量创建了精神病生物型。这些生物型与DSM诊断的精神分裂症、分裂情感性障碍和双相情感障碍相吻合。最近发展的两种多基因风险评分(PRSs)的事后祖先调整方法产生了祖先调整的PRSs (AAPRSs),它允许对多祖先样本进行PRS分析。应用于精神分裂症PRS,我们发现Khera AAPRS方法与Ge方法相比具有优越的可移植性和相当的预测精度。精神障碍的三种生物型具有相似的AAPRSs。在生物型的基因组分析中,在成人大脑和胎儿大脑中遗传调控表达(GReX)的转录组全关联研究(TWAS)中,12个基因和同种异构体显示出与特定生物型的显著基因组关联。通过在关联分析中纳入基因型主成分来解决TWAS膨胀问题。这12个基因/同型异构体中有7个满足孟德尔随机化(MR)的假定因果关系标准,包括4个基因TMEM140、ARTN、C1orf115、CYREN,以及3个转录本ENSG00000272941、ENSG00000257176、ENSG00000287733。这些基因在转染(RET)信号传导、神经细胞粘附分子1 (NCAM1)相互作用和神经突起生长的NCAM信号传导过程中的重排生物学途径中富集。与生物型的特殊关联表明,分别分析生物型可能有利于药理学临床试验和生物学研究。
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Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes, and isoforms showed significant genomic associations with specific Biotypes in a Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in the adult brain and fetal brain. TWAS inflation was addressed by the inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes TMEM140, ARTN, C1orf115, CYREN, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.

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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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