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Background: Neuromorphological changes are consistently reported in the prefrontal cortex of patients with stress-related disorders and in rodent stress models, but the effects of stress on astrocyte morphology and the potential link to behavioral deficits are relatively unknown., Methods: To answer these questions, transgenic mice expressing green fluorescent protein (GFP) under the glial fibrillary acid protein (GFAP) promotor were subjected to 7, 21, or 35 days of chronic restraint stress (CRS). CRS-induced behavioral effects on anhedonia- and anxiety-like behaviors were measured using the sucrose intake and the PhenoTyper tests, respectively. Prefrontal cortex GFP+ or GFAP+ cell morphology was assessed using Sholl analysis, and associations with behavior were determined using correlation analysis., Results: CRS-exposed male and female mice displayed anxiety-like behavior at 7, 21, and 35 days and anhedonia-like behavior at 35 days. Analysis of GFAP+ cell morphology revealed significant atrophy of distal processes following 21 and 35 days of CRS. CRS induced similar decreases in intersections at distal radii for GFP+ cells accompanied by increased proximal processes. In males, the number of intersections at the most distal radius step significantly correlated with anhedonia-like behavior (r = 0.622, P < .05) for GFP+ cells and with behavioral emotionality calculated by z-scoring all behavioral measured deficits (r = -0.667, P < .05). Similar but not significant correlations were observed in females. No correlation between GFP+ cell atrophy with anxiety-like behavior was found., Conclusion: Chronic stress exposure induces a progressive atrophy of cortical astroglial cells, potentially contributing to maladaptive neuroplastic and behavioral changes associated with stress-related disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

The orbitofrontal cortex (OFC) is vulnerable to normal and pathologic aging. Currently, layer resolution large-scale proteomic studies describing "normal" age-related alterations at OFC are not available. Here, we performed a large-scale exploratory high-throughput mass spectrometry-based protein analysis on OFC layer 2/3 from 15 "young" (15-43 years) and 18 "old" (62-88 years) human male subjects. We detected 4193 proteins and identified 127 differentially expressed (DE) proteins (p-value ≤0.05; effect size >20%), including 65 up- and 62 downregulated proteins (e.g., GFAP, CALB1). Using a previously described categorization of biological aging based on somatic tissues, that is, peripheral "hallmarks of aging," and considering overlap in protein function, we show the highest representation of altered cell-cell communication (54%), deregulated nutrient sensing (39%), and loss of proteostasis (35%) in the set of OFC layer 2/3 DE proteins. DE proteins also showed a significant association with several neurologic disorders; for example, Alzheimer's disease and schizophrenia. Notably, despite age-related changes in individual protein levels, protein co-expression modules were remarkably conserved across age groups, suggesting robust functional homeostasis. Collectively, these results provide biological insight into aging and associated homeostatic mechanisms that maintain normal brain function with advancing age., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Reduced brain-derived neurotrophic factor (BDNF) may underlie age-related synaptic loss, in turn contributing to cerebral atrophy, cognitive decline, and increased risk for psychiatric disorders. However, the specific contribution of BDNF to the age-related expression changes in synaptic markers and their temporal trajectories remain uncharacterized. Using microarray data from orbitofrontal cortex of control subjects (n=209; 16-96 years), we identified genes whose expression positively correlates with BDNF (r>0.575; n=200 genes) and analyzed them for enriched biological pathways. qPCR was performed to measure the expression level of transcript variants of BDNF, NTRK2, and selected BDNF-coexpressed genes in younger and older subjects. We confirmed age-related downregulation of BDNF and show 78 of the top 200 BDNF-coexpressed genes are associated with synaptic function. Both excitatory and inhibitory synaptic genes show decreased expression with age and are positively correlated with BDNF and NTRK2 expression and negatively correlated with dominant-negative truncated NTRK2 level. Results were validated at the RNA level in an independent cohort and at the protein level for selected findings. We next tested the causal link between the correlative human findings using mice with conditional blockade of BDNF/NTRK2 signaling. Blockade of NTRK2 activity in adult mice recapitulate the age-like pattern in the expression of markers for inhibitory presynaptic but notably not for excitatory synaptic genes. Together, these findings suggest that age-dependent decrease in BDNF signaling may cause synaptic alterations through an initial and preferential effect on GABA presynaptic genes. These results have implications for neuropsychiatric disorders characterized by accelerated aging molecular profiles, such as major depression.

KALRN (KAL) is a Rho GEF that is highly involved in regulation of the actin cytoskeleton within dendrites. There are several isoforms of the protein that arise from differential splicing of KALRN's 66 exons. KAL isoforms have different functions in development. For example, overexpression of the KAL9 and KAL12 isoforms induce dendritic elongation in early development. However, in mature neurons KAL9 overexpression reduces dendritic length, a phenotype also observed in normal human ageing. We therefore hypothesized that KAL9 would have increased expression with age, and undertook to evaluate the expression of individual KALRN exons throughout the adult lifespan. Postmortem human brain grey matter from Brodmann's area (BA) 11 and BA47 derived from a cohort of 209 individuals without psychiatric or neurodegenerative disease, ranging in age from 16 to 91 years, were analysed for KALRN expression by Affymetrix exon array. Analysis of the exon array data in an isoform-specific manner, as well as confirmatory isoform-specific qPCR studies, indicated that the longer KAL9 and KAL12 isoforms demonstrated a statistically significant, but modest, increase with age. The small magnitude of the age effect suggests that inter-individual factors other than age likely contribute to a higher degree to KAL9 and KAL12 expression. In contrast to KAL9 and KAL12, global KALRN expression did not increase with age. Our work suggests that global measures of KALRN gene expression may be misleading and future studies should focus on isoform-specific quantification., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

With aging, significant changes in circadian rhythms occur, including a shift in phase toward a "morning" chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann's area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼ 10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.

Expression of brain-derived neurotrophic factor (BDNF) and somatostatin (SST) mRNAs in the brain decreases progressively and robustly with age, and lower BDNF and SST expression in the brain has been observed in many brain disorders. BDNF is known to regulate SST expression; however, the mechanisms underlying decreased expression of both genes are not understood. DNA methylation (DNAm) is an attractive candidate mechanism. To investigate the contribution of DNAm to the age-related decline in BDNF and SST expression, the Illumina Infinium HumanMethylation450 Beadchip Array was used to quantify DNAm of BDNF (26 CpG loci) and SST (9 CpG loci) in the orbital frontal cortices of postmortem brains from 22 younger (age <42 years) and 22 older individuals (age >60 years) with known age-dependent BDNF and SST expression differences. Relative to the younger individuals, 10 of the 26 CpG loci in BDNF and 8 of the 9 CpG loci in SST were significantly hypermethylated in the older individuals. DNAm in BDNF exons/promoters I, II, and IV negatively correlated with BDNF expression (r=-0.37, p<0.05; r=-0.40, p<0.05; r=-0.24, p=0.07), and DNAm in SST 5' UTR and first exon/intron negatively correlated with SST expression (r=-0.48, p<0.01; r=-0.63, p<0.001), respectively. An expanded set of BDNF- and GABA-related genes exhibited similar age-related changes in DNAm and correlation with gene expression. These results suggest that DNAm may be a proximal mechanism for decreased expression of BDNF, SST, and other BDNF- and GABA-related genes with brain aging and, by extension, for brain disorders in which their expression is decreased.

Editing of the pre-mRNA for the serotonin receptor 2C (5-HT2CR) by site-specific adenosine deamination (A-to-I pre-mRNA editing) substantially increases the functional plasticity of this key neurotransmitter receptor and is thought to contribute to homeostatic mechanisms in neurons. 5-HT2CR mRNA editing generates up to 24 different receptor isoforms. The extent of editing correlates with 5-HT2CR functional activity: more highly edited isoforms exhibit the least function. Altered 5-HT2CR editing has been reported in postmortem brains of suicide victims. We report a comparative analysis of the connections among 5-HT2CR editing, genome-wide gene expression and DNA methylation in suicide victims, individuals with major depressive disorder and non-psychiatric controls. The results confirm previous findings of an overrepresentation of highly edited mRNA variants (which encode hypoactive 5-HT2CR receptors) in the brains of suicide victims. A large set of genes for which the expression level is associated with editing was detected. This signature set of editing-associated genes is significantly enriched for genes that are involved in synaptic transmission, genes that are preferentially expressed in neurons, and genes whose expression is correlated with the level of DNA methylation. Notably, we report that the link between 5-HT2CR editing and gene expression is disrupted in suicide victims. The results suggest that the postulated homeostatic function of 5-HT2CR editing is dysregulated in individuals who committed suicide., (Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Studies of age-related molecular profiles have separately focused on the human and rodent brains, but the extent to which each organism predicts molecular events across species for the global signature of aging and for specific biological functions has only begun to be characterized. We previously showed that the molecular correlates of aging in the mouse cortex moderately, but significantly, predicted transcript changes in human frontal cortex. Using orthologous gene links between large-scale gene expression datasets, we now report a similar reciprocal human-to-mouse prediction of molecular aging in frontal cortex, but a limited and variable conservation of age-effects across a wide spectrum of biological functions. Thus, the moderate transcriptome correlations and partial functional concordance between late-life human and rodent cohorts (13-77 years in humans and 3-24 months in mice) suggest limitations of the mouse to model normal aging of the human brain cortex., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Reduced cortical γ-aminobutyric acid (GABA) levels and altered markers for subpopulations of GABA interneurons have been reported in major depressive disorder (MDD) by in-vivo brain imaging and post-mortem histological studies. Subgroups of GABA interneurons exert differential inhibitory control on principal pyramidal neurons and can be identified based on the non-overlapping expression of the calcium-binding proteins parvalbumin (PV) or calretinin (CR) or the neuropeptide somatostatin (SST). As altered markers of GABAergic functions may also be present in bipolar disorder (BPD), the specificity of particular GABA-related molecular deficits in mood disorders is not known. We used real-time quantitative polymerase chain reaction (qPCR) to assess expression levels of two GABA synthesizing enzymes (glutamate decarboxylase; GAD65 and GAD67) and of three markers of GABA neuron subpopulations (PV, CR, SST) in the dorsolateral prefrontal cortex (DLPFC; Brodmann area 9) in triads (n=19) of control subjects and matched subjects with BPD or MDD. BPD subjects demonstrated significantly reduced PV mRNA, trend level reduction in SST mRNA and no alterations in GAD67, GAD65, or CR mRNA levels; MDD subjects demonstrated reduced SST mRNA expression without alterations in the other transcripts. The characteristic age-related decline in SST expression was not observed in MDD, as low expression was detected across age in MDD subjects. After controlling for age, MDD subjects demonstrated significantly reduced SST mRNA expression. Decreased SST levels in MDD were confirmed at the protein precursor level. Results were not explained by other clinical, demographic or technical parameters. In summary, MDD was characterized by low DLPFC SST, whereas decreased PV mRNA appears to distinguish BPD from MDD.

The activity-dependent transcription factor zif268 is re-activated in sleep following hippocampal long-term potentiation (LTP). However, the activation of secondary genes, possibly involved in modifying local synaptic strengths and ultimately stabilizing memory traces during sleep, has not yet been studied. Here, we investigated changes in hippocampal and cortical gene expression at a time point subsequent to the previously reported initial zif268 re-activation during sleep. Rats underwent unilateral hippocampal LTP and were assigned to SLEEP or AWAKE groups. Eighty minutes after a long rapid-eye-movement sleep (REMS) episode (or an equivalent amount of time for awake group) animals had their hippocampi dissected and processed for gene microarray hybridization. Prefrontal and parietal cortices were also collected for qRT-PCR analysis. The microarray analysis identified 28 up-regulated genes in the hippocampus: 11 genes were enhanced in the LTPed hemisphere of sleep animals; 13 genes were enhanced after sleep, regardless of hemisphere; and 4 genes were enhanced in LTPed hemisphere, regardless of behavioral state. qRT-PCR analysis confirmed the up-regulation of aif-1 and sc-65 during sleep. Moreover, we observed a down-regulation of the purinergic receptor, P2Y4R in the LTP hemisphere of awake animals and a trend for the protein kinase, CaMKI to be up-regulated in the LTP hemisphere of sleep animals. In the prefrontal cortex, we showed a significant LTP-dependent down-regulation of gluR1 and spinophilin specifically during sleep. Zif268 was down-regulated in sleep regardless of the hemisphere. No changes in gene expression were observed in the parietal cortex. Our findings indicate that a set of synaptic plasticity-related genes have their expression modulated during sleep following LTP, which can reflect biochemical events associated with reshaping of synaptic connections in sleep following learning.

Background: Aging leads to morphologic and functional changes in the brain and is associated with increased risk for psychiatric and neurological disorders., Methods: To identify age-related transcriptional changes in the human brain, we profiled gene expression in two prefrontal cortex (PFC) areas in postmortem samples from 39 subjects, ranging in age from 13 to 79 years., Results: Robust transcriptional age-related changes were identified for at least 540 genes. Gene expression correlates of aging were highly specific, and the large majority of the 22,000 transcripts investigated were unaffected by age. Across subjects, changes were progressive throughout adult life and accurately predicted chronological age. Age-upregulated transcripts were mostly of glial origin and related to inflammation and cellular defenses, whereas downregulated genes displayed mostly neuron-enriched transcripts relating to cellular communication and signaling., Conclusions: Continuous changes in gene expression with increasing age revealed a "molecular profile" of aging in human PFC. The restricted scope of the transcript changes suggests cellular populations or functions that are selectively vulnerable during aging. Because age-related gene expression changes begin early in adulthood and are continuous throughout life, our results suggest the possibility of identifying early cellular mechanisms that may be engaged in preventive or detrimental age-related brain functions.

One of the challenges in the analysis of gene expression data is placing the results in the context of other data available about genes and their relationships to each other. Here, we approach this problem in the study of gene expression changes associated with age in two areas of the human prefrontal cortex, comparing two computational methods. The first method, "overrepresentation analysis" (ORA), is based on statistically evaluating the fraction of genes in a particular gene ontology class found among the set of genes showing age-related changes in expression. The second method, "functional class scoring" (FCS), examines the statistical distribution of individual gene scores among all genes in the gene ontology class and does not involve an initial gene selection step. We find that FCS yields more consistent results than ORA, and the results of ORA depended strongly on the gene selection threshold. Our findings highlight the utility of functional class scoring for the analysis of complex expression data sets and emphasize the advantage of considering all available genomic information rather than sets of genes that pass a predetermined "threshold of significance."

Mood disorders are a major cause of disability. Etiology includes genetic and environmental factors, but the responsible genes have yet to be identified. Using DNA microarrays, we have conducted a large-scale gene expression analysis, in two regions of the human prefrontal cortex from post-mortem matched groups of subjects with major depression who had died by suicide, and control subjects who died from other causes and were free from psychiatric disorders. Bioinformatic analysis was used to investigate molecular and cellular pathways potentially involved in depression and suicidal behavior. We tested several hypotheses of disease pathology and of their putative molecular impact, including changes in single genes, the existence of subgroups of patients or disease subtypes, or the possibility of common biological pathways being affected in the disease process. Within the analytical limits of this relatively large genomic study, we found no evidence for molecular differences that correlated with depression and suicide, suggesting a pathology that is below the detection level of current genomic approaches, or that is either localized to other brain areas, or more associated with post-transcriptional effects and/or changes in protein levels or functions, rather than altered transcriptome in the prefrontal cortex.

Background: Genomic studies of complex tissues pose unique analytical challenges for assessment of data quality, performance of statistical methods used for data extraction, and detection of differentially expressed genes. Ideally, to assess the accuracy of gene expression analysis methods, one needs a set of genes which are known to be differentially expressed in the samples and which can be used as a "gold standard". We introduce the idea of using sex-chromosome genes as an alternative to spiked-in control genes or simulations for assessment of microarray data and analysis methods., Results: Expression of sex-chromosome genes were used as true internal biological controls to compare alternate probe-level data extraction algorithms (Microarray Suite 5.0 [MAS5.0], Model Based Expression Index [MBEI] and Robust Multi-array Average [RMA]), to assess microarray data quality and to establish some statistical guidelines for analyzing large-scale gene expression. These approaches were implemented on a large new dataset of human brain samples. RMA-generated gene expression values were markedly less variable and more reliable than MAS5.0 and MBEI-derived values. A statistical technique controlling the false discovery rate was applied to adjust for multiple testing, as an alternative to the Bonferroni method, and showed no evidence of false negative results. Fourteen probesets, representing nine Y- and two X-chromosome linked genes, displayed significant sex differences in brain prefrontal cortex gene expression., Conclusion: In this study, we have demonstrated the use of sex genes as true biological internal controls for genomic analysis of complex tissues, and suggested analytical guidelines for testing alternate oligonucleotide microarray data extraction protocols and for adjusting multiple statistical analysis of differentially expressed genes. Our results also provided evidence for sex differences in gene expression in the brain prefrontal cortex, supporting the notion of a putative direct role of sex-chromosome genes in differentiation and maintenance of sexual dimorphism of the central nervous system. Importantly, these analytical approaches are applicable to all microarray studies that include male and female human or animal subjects.

Background: The cell cycle is a critical mechanism for proper cellular growth, development and viability. The p16INK4a and p21Waf1/Cip1 are important regulators of the cell cycle progression in response to internal and external stimuli (e.g., stress). Accumulating evidence indicates that the prefrontal cortex (PFC) is particularly vulnerable to stress, where stress induces, among others, molecular and morphological alterations, reflecting behavioral changes. Here, we investigated if the p16INK4a and p21Waf1/Cip1 expression are associated with behavioral outcomes. Methods: Prefrontal cortex mRNA and protein levels of p16INK4A and p21Waf1/Cip1 of mice (six independent groups of C57BL/6J, eight mice/group, 50% female) exposed from 0 to 35 days of chronic restraint stress (CRS) were quantified by qPCR and Western Blot, respectively. Correlation analyses were used to investigate the associations between cyclin-dependent kinase inhibitors (CKIs) expression and anxiety- and depression-like behaviors. Results: Our results showed that the PFC activated the cell cycle regulation pathways mediated by both CKIs p16INK4A and p21Waf1/Cip1 in mice exposed to CRS, with overall decreased mRNA expression and increased protein expression. Moreover, correlation analysis revealed that mRNA and protein levels are statistically significant correlated with anxiety and depressive-like behavior showing a greater effect in males than females. Conclusion: Our present study extends the existing literature providing evidence that PFC cells respond to chronic stress exposure by overexpressing CKIs. Furthermore, our findings indicated that abnormal expression of p16INK4A and p21Waf1/Cip1 may significantly contribute to non-adaptive behavioral responses. [ABSTRACT FROM AUTHOR]

Genome-wide expression profiling of the human brain has revealed genes that are differentially expressed across the lifespan. Characterizing these genes adds to our understanding of both normal functions and pathological conditions. Additionally, the specific cell-types that contribute to the motor, sensory and cognitive declines during aging are unclear. Here we test if age-related genes show higher expression in specific neural cell types. Our study leverages data from two sources of murine single-cell expression data and two sources of age-associations from large gene expression studies of postmortem human brain. We used nonparametric gene set analysis to test for age-related enrichment of genes associated with specific cell-types; we also restricted our analyses to specific gene ontology groups. Our analyses focused on a primary pair of single-cell expression data from the mouse visual cortex and age-related human post-mortem gene expression information from the orbitofrontal cortex. Additional pairings that used data from the hippocampus, prefrontal cortex, somatosensory cortex and blood were used to validate and test specificity of our findings. We found robust age-related up-regulation of genes that are highly expressed in oligodendrocytes and astrocytes, while genes highly expressed in layer 2/3 glutamatergic neurons were down-regulated across age. Genes not specific to any neural cell type were also down-regulated, possibly due to the bulk tissue source of the age-related genes. A gene ontology-driven dissection of the cell-type enriched genes highlighted the strong down-regulation of genes involved in synaptic transmission and cell-cell signaling in the Somatostatin (Sst) neuron subtype that expresses the cyclin dependent kinase 6 (Cdk6) and in the vasoactive intestinal peptide (Vip) neuron subtype expressing myosin binding protein C, slow type (Mybpc1). These findings provide new insights into cell specific susceptibility to normal aging, and suggest age-related synaptic changes in specific inhibitory neuron subtypes. [ABSTRACT FROM AUTHOR]

With aging, significant changes in circadian rhythms occur, including a shift in phase toward a "morning" chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann's area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ~10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life. [ABSTRACT FROM AUTHOR]

Abstract: Aging of the human brain is associated with “normal” functional, structural, and molecular changes that underlie alterations in cognition, memory, mood and motor function, amongst other processes. Normal aging also imposes a robust constraint on the onset of many neurological diseases, ranging from late onset neurodegenerative diseases, such as Alzheimer''s (AD) and Parkinson''s diseases (PD), to early onset psychiatric disorders, such as bipolar disorder (BPD) and schizophrenia (SCZ). The molecular mechanisms and genetic underpinnings of age-related changes in the brain are understudied, and, while they share some overlap with peripheral mechanisms of aging, many are unique to the largely non-mitotic brain. Hence, understanding mechanisms of brain aging and identifying associated modulators may have profound consequences for the prevention and treatment of age-related impairments and diseases. Here we review current knowledge on age-related functional and structural changes, their molecular and genetic underpinnings, and discuss how these pathways may contribute to the vulnerability to develop age-related neurological diseases. We highlight recent findings from human post-mortem brain microarray studies, which we hypothesize, point to a potential genetically controlled transcriptional program underlying molecular changes and age-gating of neurological diseases. Finally, we discuss the implications of this model for understanding basic mechanisms of brain aging and for the future investigation of therapeutic approaches. [Copyright &y& Elsevier]

In geriatric depression, antidepressant treatment response is often slow and incomplete; new biomarkers for antidepressant response could lead to precision medicine and uncover new mechanisms of illness. Therefore, we conducted a Genome-Wide Association Study (GWAS) in older adults treated with venlafaxine. Three-hundred and fifty participants (>60 years) of mixed ethnic ancestry, diagnosed with major depression (MADRS>15), were treated with venlafaxine (~12 weeks). Individuals were genotyped using the Illumina PsychArray, and genetic data was imputed to 7.5 million variants per individual. Associations with remission status (MADRS≤10) and change in MADRS score were conducted using logistic/ linear regressions, adjusted for ancestry, sex, recruitment site, length in treatment, depressive episode duration, and baseline depressive severity. We also conducted pathway enrichment analysis using DEPICT. Our top hits in association with MADRS score change were with variants near MIR1246 and in ERBB4, a schizophrenia susceptibility gene. ERBB4 has been implicated in post-ketamine treatment down regulation of GABA and glutamate levels in the rat prefrontal cortex and hippocampus, resulting in an antidepressant effect. We also observed a suggestive association between remission status and a variant in phosphodiesterase gene PDE9A, suggesting a role in synaptic neurotransmitter signaling. Our top hit pathways included processes in the metabolic pathway of amyloid precursor protein. However, no variants survived corrections for multiple testing (p<5×10-8). Our findings suggest novel gene variant associations with measures of venlafaxine remission in older adults, as well as interesting neuro-relevant genetic pathways. A new, larger study of geriatric depression treatment will confirm these novel findings. [ABSTRACT FROM AUTHOR]