Poblete Guillermo, Nguyen Tien, Gosnell Savannah, Sofela Olutayo, Patriquin Michelle, Mathew Sanjay J, Swann Alan, Nielsen David A, Kosten Thomas R, Salas Ramiro
The Menninger Clinic, Houston, TX, USA.
Universidad de Buenos Aires, Buenos Aires, Argentina.
Chronic Stress (Thousand Oaks). 2022 Mar 21;6:24705470221083700. doi: 10.1177/24705470221083700. eCollection 2022 Jan-Dec.
Brain imaging and genetics are fields acquiring data at increasing speed, but more information does not always result in a better understanding of the underlying biology. We developed the ProcessGeneLists (PGL) approach to use genetics and mRNA gene expression data to generate regions of interest for imaging studies.
We applied PGL to past suicide attempt (ATT): We averaged the mRNA expression levels of genes (n = 130) possibly associated with ATT (p ≤ 10 in a published genome-wide association study, GWAS) in each brain region studied in the Human Allen Brain Atlas (6 ex-vivo brains, 158 to 946 regions/brain have mRNA expression data) and compared that to the averaged mRNA expression levels of all other genes in each region in each brain in the atlas.
PGL revealed 8 regions where "attempt-related genes" were differentially expressed (Wilcoxon test with Bonferroni correction 8.88 = <p < = 0.046). Using resting state functional connectivity (RSFC), we studied those regions in psychiatric inpatients (male/female, n = 132 with [ATT], n = 291 without [NAT] past attempt, unrelated to those in the GWAS).Among the 8 PGL-identified regions, the subiculum showed higher RSFC with habenula (p < 10) and dorsolateral prefrontal cortex (dlPFC p < 0.05) in ATT. We genotyped one single nucleotide polymorphism (SNP) in each of the five genes (within 130 from GWAS) with most important subicular expression. AKAP7 (A-Kinase Anchoring Protein 7, important in hippocampal memory processes) showed an interaction between genotype, ATT, and subiculum/dlPFC RSFC.
PGL uncovered a brain function/genotype interaction in ATT by using published GWAS data to inform imaging studies. This could inform individualized therapies in the future.
脑成像和遗传学领域正在以越来越快的速度获取数据，但更多的信息并不总是能带来对潜在生物学机制更好的理解。我们开发了过程基因列表（PGL）方法，以利用遗传学和mRNA基因表达数据来生成用于成像研究的感兴趣区域。
我们将PGL应用于既往自杀未遂（ATT）：我们对可能与ATT相关的基因（n = 130，在一项已发表的全基因组关联研究（GWAS）中p≤10）在人类艾伦脑图谱研究的每个脑区中的mRNA表达水平进行平均（6个离体大脑，每个大脑有158至946个区域有mRNA表达数据），并将其与图谱中每个大脑每个区域中所有其他基因的平均mRNA表达水平进行比较。
PGL揭示了8个区域，其中“未遂相关基因”存在差异表达（经Bonferroni校正的Wilcoxon检验，8.88 = <p <= 0.046）。使用静息态功能连接（RSFC），我们在精神科住院患者中研究了这些区域（男性/女性，n = 132有[ATT]，n = 291无既往未遂[NAT]，与GWAS中的无关）。在PGL识别的8个区域中，在ATT中，海马下脚与缰核（p < 10）和背外侧前额叶皮层（dlPFC，p < 0.05）的RSFC更高。我们对五个基因（来自GWAS的130个基因内）中每个基因的一个单核苷酸多态性（SNP）进行了基因分型，这些基因在海马下脚表达最为重要。AKAP7（A激酶锚定蛋白7，在海马记忆过程中起重要作用）显示出基因型、ATT和海马下脚/dlPFC RSFC之间的相互作用。
PGL通过使用已发表的GWAS数据为成像研究提供信息，揭示了ATT中的脑功能/基因型相互作用。这可能为未来的个体化治疗提供依据。
