A Novel Approach to Link Genetics and Human MRI Identifies AKAP7-Dependent Subicular/Prefrontal Functional Connectivity as Altered in Suicidality.
A Novel Approach to Link Genetics and Human MRI Identifies AKAP7-Dependent Subicular/Prefrontal Functional Connectivity as Altered in Suicidality.
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DOI：
10.1177/24705470221083700
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
Salas R
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文献类型：
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作者：
Poblete G;Nguyen T;Gosnell S;Sofela O;Patriquin M;Mathew SJ;Swann A;Nielsen DA;Kosten TR;Salas R
大脑成像和遗传学是以越来越快的速度获取数据的领域，但更多的信息并不总是导致对潜在生物学的更好理解。我们开发了ProcessGeneLists（PGL）方法，使用遗传学和mRNA基因表达数据来生成成像研究的感兴趣区域。我们将PGL应用于过去的自杀企图（ATT）：我们对可能与ATT相关的基因（n = 130）的mRNA表达水平进行平均，（已发表的全基因组关联研究，GWAS中p ≤ 10−3）在人类艾伦脑图谱中研究的每个脑区中（6个离体脑，158至946个区域/脑有mRNA表达数据）并将其与图谱中每个大脑中每个区域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“与肿瘤相关的基因”差异表达（Wilcoxon检验，Bonferroni校正8.88 - 11 = <p < = 0.046）。使用静息状态功能连接（RSFC），我们研究了精神病住院患者（男性/女性，n = 132与[ATT]，n = 291没有[NAT]过去的尝试，与GWAS无关）的这些区域。在8个PGL识别的区域中，下托与缰（p < 10−6）和背外侧前额叶皮层（dlPFC pFWE < 0.05）在ATT中显示出更高的RSFC。我们对5个基因（来自GWAS的130个基因内）中的每一个进行了单核苷酸多态性（SNP）基因分型，这些基因具有最重要的海马下托表达。AKAP 7（A-激酶调节蛋白7，在海马记忆过程中很重要）显示了基因型、ATT和下托/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。这可以为未来的个性化治疗提供信息。
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 ≤ 10−3 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 8.88−11 = <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 < 10−6) and dorsolateral prefrontal cortex (dlPFC pFWE < 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.