Neurexin 1 variants as risk factors for suicide death.

Suicide is a significant public health concern with complex etiology. Although the genetic component of suicide is well established, the scope of gene networks and biological mechanisms underlying suicide has yet to be defined. Previously, we reported genome-wide evidence that neurexin 1 (NRXN1), a key synapse organizing molecule, is associated with familial suicide risk. Here we present new evidence for two non-synonymous variants (rs78540316; P469S and rs199784139; H885Y) associated with increased familial risk of suicide death. We tested the impact of these variants on binding interactions with known partners and assessed functionality in a hemi-synapse formation assay. Although the formation of hemi-synapses was not altered with the P469S variant relative to wild-type, both variants increased binding to the postsynaptic binding partner, leucine-rich repeat transmembrane neuronal 2 (LRRTM2) in vitro. Our findings indicate that variants in NRXN1 and related synaptic genes warrant further study as risk factors for suicide death.

Altered transcriptomes, cell type proportions, and dendritic spine morphology in hippocampus of suicide decedents.

BACKGROUND: Suicide is a manner of death resulting from complex environmental and genetic risks that affect millions of people globally. Both structural and functional studies identified the hippocampus as one of the vulnerable brain regions contributing to suicide risk. METHODS: We have identified the hippocampal tissue transcriptomes, gene ontology, cell type proportions, and dendritic spine morphology in controls (n = 28) and suicide decedents (n = 22). In addition, the transcriptomic signature in iPSC-derived neuronal precursor cells (NPCs) and neurons were also investigated in controls (n = 2) and suicide decedents (n = 2). RESULTS: The hippocampal tissue transcriptomic data revealed that NPAS4 gene expression was downregulated while ALDH1A2, NAAA, and MLXIPL gene expressions were upregulated in hippocampal tissue of suicide decedents. The gene ontology identified 29 significant pathways including NPAS4-associated gene ontology terms "excitatory post-synaptic potential", "regulation of postsynaptic membrane potential" and "long-term memory" indicating alteration of glutamatergic synapses in the hippocampus of suicide decedents. The cell type deconvolution identified decreased excitatory neuron proportion and an increased inhibitory neuron proportion providing evidence of excitation/inhibition imbalance in the hippocampus of suicide decedents. In addition, suicide decedents had increased dendric spine density in the hippocampus, due to an increase of thin (relatively unstable) dendritic spines, compared to controls. The transcriptomes of iPSC-derived hippocampal-like NPCs and neurons revealed 31 and 33 differentially expressed genes in NPC and neurons, respectively, of suicide decedents. CONCLUSIONS: Our findings will provide new insights into the hippocampal neuropathology of suicide.

Altered transcriptomes, cell type proportions, and dendritic spine morphology in hippocampus of suicide deaths.

Suicide is a condition resulting from complex environmental and genetic risks that affect millions of people globally. Both structural and functional studies identified the hippocampus as one of the vulnerable brain regions contributing to suicide risk. Here, we have identified the hippocampal transcriptomes, gene ontology, cell type proportions, dendritic spine morphology, and transcriptomic signature in iPSC-derived neuronal precursor cells (NPCs) and neurons in postmortem brain tissue from suicide deaths. The hippocampal tissue transcriptomic data revealed that NPAS4 gene expression was downregulated while ALDH1A2, NAAA, and MLXIPL gene expressions were upregulated in tissue from suicide deaths. The gene ontology identified 29 significant pathways including NPAS4-associated gene ontology terms "excitatory post-synaptic potential", "regulation of postsynaptic membrane potential" and "long-term memory" indicating alteration of glutamatergic synapses in the hippocampus of suicide deaths. The cell type deconvolution identified decreased excitatory neuron proportion and an increased inhibitory neuron proportion providing evidence of excitation/inhibition imbalance in the hippocampus of suicide deaths. In addition, suicide deaths had increased dendric spine density, due to an increase of thin (relatively unstable) dendritic spines, compared to controls. The transcriptomes of iPSC-derived hippocampal-like NPCs and neurons revealed 31 and 33 differentially expressed genes in NPC and neurons, respectively, of suicide deaths. The suicide-associated differentially expressed genes in NPCs were RELN, CRH, EMX2, OXTR, PARM1 and IFITM2 which overlapped with previously published results. The previously-known suicide-associated differentially expressed genes in differentiated neurons were COL1A1, THBS1, IFITM2, AQP1, and NLRP2. Together, these findings would help better understand the hippocampal neurobiology of suicide for identifying therapeutic targets to prevent suicide.

Genome-Wide Association Study of Suicide Death and Polygenic Prediction of Clinical Antecedents.

OBJECTIVE: Death by suicide is a highly preventable yet growing worldwide health crisis. To date, there has been a lack of adequately powered genomic studies of suicide, with no sizable suicide death cohorts available for analysis. To address this limitation, the authors conducted the first comprehensive genomic analysis of suicide death using previously unpublished genotype data from a large population-ascertained cohort. METHODS: The analysis sample comprised 3,413 population-ascertained case subjects of European ancestry and 14,810 ancestrally matched control subjects. Analytical methods included principal component analysis for ancestral matching and adjusting for population stratification, linear mixed model genome-wide association testing (conditional on genetic-relatedness matrix), gene and gene set-enrichment testing, and polygenic score analyses, as well as single-nucleotide polymorphism (SNP) heritability and genetic correlation estimation using linkage disequilibrium score regression. RESULTS: Genome-wide association analysis identified two genome-wide significant loci (involving six SNPs: rs34399104, rs35518298, rs34053895, rs66828456, rs35502061, and rs35256367). Gene-based analyses implicated 22 genes on chromosomes 13, 15, 16, 17, and 19 (q<0.05). Suicide death heritability was estimated at an h2SNP value of 0.25 (SE=0.04) and a value of 0.16 (SE=0.02) when converted to a liability scale. Notably, suicide polygenic scores were significantly predictive across training and test sets. Polygenic scores for several other psychiatric disorders and psychological traits were also predictive, particularly scores for behavioral disinhibition and major depressive disorder. CONCLUSIONS: Multiple genome-wide significant loci and genes were identified and polygenic score prediction of suicide death case-control status was demonstrated, adjusting for ancestry, in independent training and test sets. Additionally, the suicide death sample was found to have increased genetic risk for behavioral disinhibition, major depressive disorder, depressive symptoms, autism spectrum disorder, psychosis, and alcohol use disorder compared with the control sample.

Preliminary findings of noncompliance with psychotropic medication and prevalence of methamphetamine intoxication associated with suicide completion.

OBJECTIVE: A study of medical examiner records from suicide completers was designed to identify potential precipitating factors in the decision to commit suicide. METHODS: Forensic data has been collected for a subset of suicide victims in Utah who completed suicide between 1996 and 2002. RESULTS: Youth suicide completers appear to be undiagnosed for mental illness, or to be noncompliant with psychotropic medications. Along with treatment issues, alcohol and methamphetamine were the most common substances found in the blood and/or urine of suicide completers. CONCLUSIONS: Accurate diagnosis of mental illness, and improved compliance with psychotropic medications may play a critical role in suicide prevention. The prevalence of methamphetamine in suicide completers is unexpectedly high and requires further investigation.

Comparative analysis of suicide, accidental, and undetermined cause of death classification.

Suicide determination is not standardized across medical examiners, and many suspected suicides are later classified as accidental or undetermined. The present study investigated patterns between these three groups using a medical examiner database and 633 structured interviews with next of kin. There were similarities across all three classification groups, including rates of mental illness and psychiatric symptoms. Those classified suicide were more likely to be male, to have died in a violent fashion, and have a stronger family history of suicide. Chronic pain was very common across all three groups, but significantly higher in the accidental and undetermined groups.