A Novel Approach to Link Genetics and Human MRI Identifies AKAP7-Dependent Subicular/Prefrontal Functional Connectivity as Altered in Suicidality

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

miR-124-3p target genes identify globus pallidus role in suicide ideation recovery in borderline personality disorder

“…A less well-recognized role of the GP may be in emotional processing and behavior. Projections from the GP internal segment to the lateral habenula (LHb) have been described and may be critical for the reward system 37 , and we have shown that the habenula is a likely important brain locus in suicidality 12 , 16 . Future studies on BPD behaviors should consider focusing on the compensatory mechanisms converging on GP and LHb connectivity that may result in alleviated BFI personality features.…”

The Habenula in Mood Disorders: A Scoping Review of Human Studies

“…Another one used a seed-to-voxel analysis where voxels within specific ROIs were considered in addition to ROI-to-ROI analyses (Jung et al, 2022). Three studies exclusively performed ROI-to-ROI analyses (Amiri et al, 2023;Gosnell et al, 2019;Poblete et al, 2022). Lastly, two studies opted for network analysis (Amiri et al, 2021;Zhu et al, 2019), which is a framework that envisions the brain as an intricate network.…”