Xia Cuihua, Alliey-Rodriguez Ney, Tamminga Carol A, Keshavan Matcheri S, Pearlson Godfrey D, Keedy Sarah K, Clementz Brett, McDowell Jennifer E, Parker David, Lencer Rebekka, Hill S Kristian, Bishop Jeffrey R, Ivleva Elena I, Wen Cindy, Dai Rujia, Chen Chao, Liu Chunyu, Gershon Elliot S
MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
Mol Psychiatry. 2025 Jun;30(6):2673-2685. doi: 10.1038/s41380-024-02876-z. Epub 2024 Dec 21.
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.
双相情感障碍 - 精神分裂症中间表型网络（B - SNIP）基于多血统样本中的神经生物学测量结果创建了精神病生物型。这些生物型跨越了精神分裂症、分裂情感性障碍和伴有精神病性症状的双相情感障碍的《精神疾病诊断与统计手册》（DSM）诊断。两种最近开发的多基因风险评分（PRS）事后血统调整方法生成了血统调整后的PRS（AAPRS），这使得能够对多血统样本进行PRS分析。应用于精神分裂症PRS时，我们发现与Ge方法相比，Khera AAPRS方法具有更高的可移植性和相当的预测准确性。三种精神病性障碍的生物型在不同血统中具有相似的AAPRS。在生物型的基因组分析中，在成人脑和胎儿脑的基因调控表达（GReX）的全转录组关联研究（TWAS）中，12个基因及其异构体显示出与特定生物型有显著的基因组关联。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/异构体中的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。这些基因在转染重排（RET）信号传导、神经细胞粘附分子1（NCAM1）相互作用以及神经突生长的NCAM信号传导的生物学途径中富集。与生物型的特定关联表明，药理临床试验和生物学研究可能会从分别分析生物型中受益。
