Bhattacharyya Upasana, John Jibin, Lencz Todd, Lam Max
Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY.
Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY.
medRxiv. 2024 Apr 16:2024.04.16.24305885. doi: 10.1101/2024.04.16.24305885.
Given the increasingly large number of loci discovered by psychiatric GWAS, specification of the key biological pathways underlying these loci has become a priority for the field. We have previously leveraged the pleiotropic genetic relationships between schizophrenia and two cognitive phenotypes (educational attainment and cognitive task performance) to differentiate two subsets of illness-relevant SNPs: (1) those with "concordant" alleles, which are associated with reduced cognitive ability/education and increased schizophrenia risk; and (2) those with "discordant" alleles linked to reduced educational and/or cognitive levels but lower schizophrenia susceptibility. In the present study, we extend our prior work, utilizing larger input GWAS datasets and a more powerful statistical approach to pleiotropic meta-analysis, the Pleiotropic Locus Exploration and Interpretation using Optimal test (PLEIO). Our pleiotropic meta-analysis of schizophrenia and the two cognitive phenotypes revealed 768 significant loci (159 novel). Among these, 347 loci harbored concordant SNPs, 270 encompassed discordant SNPs, and 151 "dual" loci contained concordant and discordant SNPs. Competitive gene-set analysis using MAGMA related concordant SNP loci with neurodevelopmental pathways (e.g., neurogenesis), whereas discordant loci were associated with mature neuronal synaptic functions. These distinctions were also observed in BrainSpan analysis of temporal enrichment patterns across developmental periods, with concordant loci containing more prenatally expressed genes than discordant loci. Dual loci were enriched for genes related to mRNA translation initiation, representing a novel finding in the schizophrenia literature.
鉴于精神疾病全基因组关联研究（GWAS）发现的基因座数量日益增多，明确这些基因座背后的关键生物学途径已成为该领域的首要任务。我们之前利用精神分裂症与两种认知表型（教育程度和认知任务表现）之间的多效性遗传关系，区分了与疾病相关的单核苷酸多态性（SNP）的两个子集：（1）具有“一致”等位基因的SNP，它们与认知能力/教育程度降低以及精神分裂症风险增加相关；（2）具有“不一致”等位基因的SNP，它们与教育程度和/或认知水平降低但精神分裂症易感性较低相关。在本研究中，我们扩展了之前的工作，使用了更大的输入GWAS数据集和一种更强大的多效性荟萃分析统计方法——使用最优检验的多效性基因座探索与解释（PLEIO）。我们对精神分裂症和这两种认知表型进行的多效性荟萃分析揭示了768个显著基因座（159个为新发现）。其中，347个基因座含有一致的SNP，270个包含不一致的SNP，151个“双重”基因座同时包含一致和不一致的SNP。使用MAGMA进行的竞争性基因集分析表明，一致的SNP基因座与神经发育途径（如神经发生）相关，而不一致的基因座与成熟神经元的突触功能相关。在对不同发育时期的时间富集模式进行的BrainSpan分析中也观察到了这些差异，一致的基因座比不一致的基因座含有更多产前表达的基因。双重基因座富含与mRNA翻译起始相关的基因，这是精神分裂症文献中的一个新发现。
