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

Chronic Stress (Thousand Oaks). 2022 Mar 21;6:24705470221083700. doi: 10.1177/24705470221083700. eCollection 2022 Jan-Dec.


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.

Keywords: AKAP-7; dorsolateral prefrontal cortex; habenula; resting state functional connectivity; subiculum; suicide.