Elliot C. Nelson

Background: Marital transitions and stability are key social determinants of alcohol use, yet their impact across different life stages remains underexplored. This study utilizes a lifespan‐oriented approach to examine longitudinal associations between marital status and alcohol consumption and problems and to investigate underlying sex differences. Methods: Longitudinal data from two components (early mid‐life and later‐life) of the Collaborative Study on the Genetics of Alcoholism (COGA) were included, with participants averaging 33 (early mid‐life) and 62 (later‐life) years of age at their last interview. Participants were categorized into distinct groups based on their marital history across assessment waves: persistently married (reference), never married, divorced/separated, widowed, and three transition groups (into marriage, out of marriage, and mixed transitions). Alcohol use measures included past 12‐month alcohol symptom counts, past 6‐month typical drinks per week, and past 6‐month maximum drinks consumed in 24 h. Generalized linear mixed models estimated cohort‐specific risks. Results: Across both cohorts, alcohol consumption declined with age, while AUD symptom counts significantly increased ( p < 0.001). In the later‐life sample, never married individuals exhibited the highest likelihood of AUD symptoms (IRR = 3.82, p < 0.001). A significant sex interaction indicated widowhood was associated with a threefold increase in AUD symptoms (IRR = 3.46, p = 0.003), whereas widowhood was relatively protective among women (reference group). In the early mid‐life sample, transitioning out of marriage emerged as a primary correlate of symptom escalation (IRR = 2.13, p < 0.001). Conclusion: Marital stability buffers against AUD problems across the lifespan. However, the risks associated with marital instability are highly specific: marital exit poses a critical threat in early mid‐life, while widowhood represents a profound vulnerability for older men. Interventions should be tailored with attention to life stage and sex‐specific risks to mitigate alcohol‐related harm during marital transitions.

Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (N _cases =33,977, N _controls =675,392) in four broad ancestry groups: European (EUR) (N _cases =22,564, N _controls =624,672), African (AFR) (N _cases =7,574, N _controls =34,189), Admixed American (AMR) (N _cases =3,657, N _controls =15,698), and East Asian (EAS) (N _cases =182, N _controls =833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2 *rs5794864, P =7.32×10 ⁻¹⁰ , one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5 *rs55781567, P =3.27×10 ⁻⁹ , two in a male-only meta-analysis, including FTO *rs8057044, P =9.50×10 ⁻⁹ , and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (N _EUR =18,841, N _AFR =12,263, N _AMR =9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1 , BSN ). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (r _g =0.94, P =5.43×10 ⁻²³⁷ ) and opioid use disorder (r _g =1.01, P =4.40×10 ⁻¹⁰⁷ ), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.

Opioid misuse remains rampant as new synthetic opioids reach the market. Large-scale genetic tools like the GWAS identify previously unrecognized targets and biomarkers in opioid misuse with the hopes of combating the opioid epidemic. One such target is the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) auxiliary protein Cornichon Homolog-3 (human analog: CNIH3, mouse analog: Cnih3), which determines AMPAR subunit composition and kinetics: important factors in opioid use. Though CNIH3 was identified as a gene of interest in OUD, its role in opioid use and related behavior has not been studied. Using mice with Cnih3 deletion, we characterize the role of Cnih3 in a battery of behaviors that encompass well-being, affect, spatial and social memory, operant learning, reversal learning, and opioid use itself. We find that Cnih3 deletion moderately impairs spatial memory in the novel object recognition task, as well as operant learning in a sucrose self-administration paradigm. Cnih3 deletion also delays acquisition of fentanyl IVSA in females and blunts fentanyl intake during IVSA in both sexes. We use principal component analysis to pinpoint the dimensions in which Cnih3 deletion impacts the behaviors tested in an unbiased manner. These findings, combined with initial GWAS findings, identify Cnih3 as a behaviorally relevant protein in opioid-related plasticity.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

The hippocampus is a critical brain region for coordinating learning, memory, and behavior. In females, the estrous cycle alters these functions through steroid hormone activity, with well-characterized effects on cellular physiology and behavior. However, the molecular basis of these outcomes has not been systematically explored. Therefore, we profiled the transcriptome of dorsal hippocampi from female mice in each estrous cycle stage, and contrasted it with that of males. We identify only subtle sex differences in gene expression between the sexes on average, yet comparing males to individual estrous stages reveals up to thousands of genes deviating from male expression patterns at specific estrous stages. These estrous-responsive genes are especially enriched in gene markers of oligodendrocytes and the dentate gyrus, and in functional gene sets relating to estrogen response, potassium channels, and synaptic gene splicing. Next we profiled Cnih3 knockouts across estrous to provide insight into their previously reported estrous-dependent phenotypes in hippocampal synaptic plasticity, composition, and learning and memory behaviors. Surprisingly, Cnih3 knockouts showed far broader transcriptomic differences between estrous cycle stages and males. Moreover, Cnih3 knockout drove subtle but extensive expression changes accenting sex differential expresssion at diestrus and estrus. Altogether, our profiling constitutes both a resource characterizing estrous-specific gene expression patterns in the adult hippocampus, which can provide insights into mechanisms of sex differential neuropsychiatric functions and dysfunctions, while also highlighting roles of Cnih3 as a buffer against transcriptional effects of estrous and providing insights into the molecular mechanisms that may underlie estrous-dependent phenotypes with its loss.

Opioid addiction (OA) has strong heritability, yet few genetic variant associations have been robustly identified. Only rs1799971, the A118G variant in OPRM1 , has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data and published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r _g > 0.9). We observed the strongest evidence to date for OPRM1 : lead SNP rs9478500 ( p =2.56×10 ⁻⁹ ). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN . Variants within these loci appear to be pleiotropic for addiction and related traits.

Attempts to identify opioid users with increased risk of escalating to opioid use disorder (OUD) have had limited success. Retrospectively assessed subjective effects of initial opioid misuse were compared in a pilot sample of opioid misusers (nonmedical use ≤60 times lifetime) who had never met criteria for OUD (N = 14) and heroin‐addicted individuals in treatment for OUD (N = 15). Relative to opioid misusers without a lifetime OUD diagnosis, individuals with OUD reported greater euphoria and other positive emotions, activation, pruritus, and internalizing symptoms. Consistent with these findings, proxy Addiction Research Center Inventory (ARCI) Amphetamine Group, and Morphine Benzedrine Group scale mean item scores were significantly higher in those with OUD. Replication was attempted in opioid misusers with (N = 25) and without OUD (N = 25) who were assessed as part of an ongoing genetic study. We observed similar significant between‐group differences in individual subjective effect items and ARCI scale mean item scores in the replication sample. We, thus confirm findings from prior reports that retrospectively assessed subjective responses to initial opioid exposure differ significantly between opioid users who do, and do not, progress to OUD. Our report extends these findings in comparisons limited to opioid misusers. Additional research will be necessary to examine prospectively whether the assessment of subjective effects after initial use has predictive utility in the identification of individuals more likely to progress to OUD.

Chronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = −5.39, p = 7.2 × 10^–8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10^–8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10^–6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10^–8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10^–7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10^–5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10^–5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10^–5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Cornichon homolog-3 (CNIH3) is an AMPA receptor (AMPAR) auxiliary protein that traffics AMPARs to the postsynaptic membrane and potentiates AMPAR signaling. AMPARs are key components of hippocampal synaptic plasticity and memory formation, however the role of CNIH3 in memory has yet to be elucidated. To study the role of CNIH3 on mouse behavior, we bred and characterized a line of Cnih3 ^-/- mice from C57BL/6 Cnih3 ^{tm1a(KOMP)Wtsi} mice obtained from the Knockout Mouse Project (KOMP). In agreement with previous studies of CNIH3 in the brain, we observed concentrated expression of Cnih3 in the dorsal hippocampus, a region associated with spatial learning and memory. Therefore, we tested Cnih3 ^+/+ , Cnih3 ^+/- , and Cnih3 ^-/- mice in the Barnes maze paradigm to measure spatial memory. We observed no change in spatial memory in male Cnih3 ^+/- and Cnih3 ^-/- mice compared to male Cnih3 ^+/+ controls, however, Cnih3 ^-/- female mice made significantly more primary errors, had a higher primary latency, and took less efficient routes to the target in the maze compared to Cnih3 ^+/+ female mice. Next, to investigate an enhancement of spatial memory by Cnih3 overexpression, specifically in the dorsal hippocampus, we developed an AAV5 viral construct to express wild-type Cnih3 in excitatory neurons. Female mice overexpressing Cnih3 made significantly fewer errors, had a lower primary latency to the target, and took more efficient routes to the maze target compared to YFP expressing control females. No change in spatial memory was observed in male Cnih3 overexpression mice. This study, the first to identify sex-specific effects of the AMPAR auxiliary protein CNIH3 on spatial memory, provides the groundwork for future studies investigating the role of CNIH3 on sexually dimorphic AMPAR-dependent behavior and hippocampal synaptic plasticity.