Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding.

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.

Light-strand bias and enriched zones of embedded ribonucleotides are associated with DNA replication and transcription in the human-mitochondrial genome.

Abundant ribonucleoside-triphosphate (rNTP) incorporation into DNA by DNA polymerases in the form of ribonucleoside monophosphates (rNMPs) is a widespread phenomenon in nature, resulting in DNA-structural change and genome instability. The rNMP distribution, characteristics, hotspots and association with DNA metabolic processes in human mitochondrial DNA (hmtDNA) remain mostly unknown. Here, we utilize the ribose-seq technique to capture embedded rNMPs in hmtDNA of six different cell types. In most cell types, the rNMPs are preferentially embedded on the light strand of hmtDNA with a strong bias towards rCMPs; while in the liver-tissue cells, the rNMPs are predominately found on the heavy strand. We uncover common rNMP hotspots and conserved rNMP-enriched zones across the entire hmtDNA, including in the control region, which links the rNMP presence to the frequent hmtDNA replication-failure events. We show a strong correlation between coding-sequence size and rNMP-embedment frequency per nucleotide on the non-template, light strand in all cell types, supporting the presence of transient RNA-DNA hybrids preceding light-strand replication. Moreover, we detect rNMP-embedment patterns that are only partly conserved across the different cell types and are distinct from those found in yeast mtDNA. The study opens new research directions to understand the biology of hmtDNA and genomic rNMPs.

Integrating human brain proteomes with genome-wide association data implicates novel proteins in post-traumatic stress disorder.

Genome-wide association studies (GWAS) have identified several risk loci for post-traumatic stress disorder (PTSD); however, how they confer PTSD risk remains unclear. We aimed to identify genes that confer PTSD risk through their effects on brain protein abundance to provide new insights into PTSD pathogenesis. To that end, we integrated human brain proteomes with PTSD GWAS results to perform a proteome-wide association study (PWAS) of PTSD, followed by Mendelian randomization, using a discovery and confirmatory study design. Brain proteomes (N = 525) were profiled from the dorsolateral prefrontal cortex using mass spectrometry. The Million Veteran Program (MVP) PTSD GWAS (n = 186,689) was used for the discovery PWAS, and the Psychiatric Genomics Consortium PTSD GWAS (n = 174,659) was used for the confirmatory PWAS. To understand whether genes identified at the protein-level were also evident at the transcript-level, we performed a transcriptome-wide association study (TWAS) using human brain transcriptomes (N = 888) and the MVP PTSD GWAS results. We identified 11 genes that contribute to PTSD pathogenesis via their respective cis-regulated brain protein abundance. Seven of 11 genes (64%) replicated in the confirmatory PWAS and 4 of 11 also had their cis-regulated brain mRNA levels associated with PTSD. High confidence level was assigned to 9 of 11 genes after considering evidence from the confirmatory PWAS and TWAS. Most of the identified genes are expressed in other PTSD-relevant brain regions and several are preferentially expressed in excitatory neurons, astrocytes, and oligodendrocyte precursor cells. These genes are novel, promising targets for mechanistic and therapeutic studies to find new treatments for PTSD.

Important Correlates of Purpose in Life in a Diverse Population-Based Cohort: A Machine Learning Approach.

BACKGROUND: Purpose-in-life (PiL) refers to the tendency to derive meaning and purpose from daily life experiences. Individuals with higher PiL were more likely to have better physical, mental, and cognitive health in prospective studies. Here, we aimed to identify important correlates of PiL among people of diverse backgrounds. METHODS: Participants were recruited by the population-based Health and Retirement Study and provided information on 34 different sociodemographic and psychosocial factors through psychometrically validated measures. To identify important correlates of PiL, we employed regularized regression implemented by Elastic Net on the entire cohort as well as among self-identified black participants only and white participants only, respectively. RESULTS: A total of 6,620 participants were included in this study, among whom 913 were black and 5,707 were white. We identified 12 and 23 important sociodemographic and psychosocial correlates of PiL among black and white participants, respectively. Notably, all the 12 correlates in black participants were also correlates among white participants. Interestingly, when we examined both black and white participants together, being black was associated with having higher PiL. The correlates with the largest effect on PiL that were shared among black and white participants were hopelessness, perceived constraint on personal control, and self-mastery. CONCLUSION: Several sociodemographic and psychosocial factors most strongly associated with PiL were shared among black and white participants. Future studies should investigate whether interventions targeting correlates of PiL can lead to higher sense of life purpose in participants of diverse backgrounds.

Next-generation sequencing errors due to genetic variation in WRAP53 encoding TCAB1 on chromosome 17.

Next-generation sequencing (NGS) is a valuable tool, but has limitations in sequencing through repetitive runs of single nucleotides (homopolymers). Pathogenic germline variants in WRAP53 encoding telomere Cajal body protein 1 (TCAB1) are a known cause of dyskeratosis congenita. We identified a significant NGS error in WRAP53, c.1562dup, p.Ala522Glyfs*8 (rs755116516 G>-/GG/GGG) that did not validate by Sanger sequencing. This error occurs because rs755116516 G>-/GG/GGG (Chr17:7,606,714) is polymorphic, and variants at this site challenge the ability of NGS to accurately call the correct number of nucleotides in a homopolymer run. This was further complicated by the fact that chr17:7,606,721 (rs769202794) is multiallelic G>A, C, T, and that chr17:7,606,722 is also multiallelic (rs7640C>A/G/T and rs373064567C>delC). In addition to the expert interpretation of potentially clinically actionable variants, it recommended that all variants in regions of the genome with homopolymers be validated by Sanger sequencing before clinical action.

Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression.

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5-12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.

Critical evaluation of copy number variant calling methods using DNA methylation.

Recent technological and methodological developments have enabled the use of array-based DNA methylation data to call copy number variants (CNVs). ChAMP, Conumee, and cnAnalysis450k are popular methods currently used to call CNVs using methylation data. However, so far, no studies have analyzed the reliability of these methods using real samples. Data from a cohort of individuals with genotype and DNA methylation data generated using the HumanMethylation450 and MethylationEPIC BeadChips were used to assess the consistency between the CNV calls generated by methylation and genotype data. We also took advantage of repeated measures of methylation data collected from the same individuals to compare the reliability of CNVs called by ChAMP, Conumee, and cnAnalysis450k for both the methylation arrays. ChAMP identified more CNVs than Conumee and cnAnalysis450k for both the arrays and, as a consequence, had a higher overlap (~62%) with the calls from the genotype data. However, all methods had relatively low reliability. For the MethylationEPIC array, Conumee had the highest reliability (57.6%), whereas for the HumanMethylation450 array, cnAnalysis450k had the highest reliability (43.0%). Overall, the MethylationEPIC array provided significant gains in reliability for CNV calling over the HumanMethylation450 array but not for overlap with CNVs called using genotype data.

PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.

Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.

Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

Important Correlates of Purpose in Life Identified Through a Machine Learning Approach.

OBJECTIVE: A wealth of evidence has linked purpose in life (PiL) to better mental and physical health and healthy aging. Here, the authors aimed to determine important correlates of PiL using a machine learning approach. METHODS: Participants were recruited from retirement communities by the Rush Memory and Aging Project and assessed for childhood experience, adulthood sociodemographic factors (e.g., education, income, marital status), lifestyle and health behavior (e.g., cognitively stimulating activities, exercise, social activities, social network size), psychological factors (e.g., depression, loneliness, perceived discrimination, perceived social support), personality traits (e.g., PiL, harm avoidance), and medical conditions. Elastic Net was implemented to identify important correlates of PiL. RESULTS: A total of 1,839 participants were included in our analysis. Among the 23 variables provided to Elastic Net, 10 were identified as important correlates of PiL. In order of decreasing effect size, factors associated with lower PiL were loneliness, harm avoidance, older age, and depressive symptoms, while those associated with greater PiL were perceived social support, more social activities, more years of education, higher income, intact late-life cognitive performance, and more middle-age cognitive activities. CONCLUSION: Our findings identify potentially important modifiable factors as targets for intervention strategies to enhance PiL.

Polygenic risk scores differentiate schizophrenia patients with toxoplasma gondii compared to toxoplasma seronegative patients.

Schizophrenia (SCZ) is an etiologically heterogeneous disease with genetic and environmental risk factors (e.g., Toxoplasma gondii infection) differing among affected individuals. Distinguishing such risk factors may point to differences in pathophysiological pathways and facilitate the discovery of individualized treatments. Toxoplasma gondii (TOXO) has been implicated in increasing the risk of schizophrenia. To determine whether TOXO-positive individuals with SCZ have a different polygenic risk burden than uninfected people, we applied the SCZ polygenic risk score (SCZ-PRS) derived from the Psychiatric GWAS Consortium separately to the TOXO-positive and TOXO-negative subjects with the diagnosis of SCZ as the outcome variable. The SCZ-PRS does not include variants in the major histocompatibility complex. Of 790 subjects assessed for TOXO, the 662 TOXO-negative subjects (50.8% with SCZ) reached a Bonferroni corrected significant association (p = 0.00017, R2 = 0.023). In contrast, the 128 TOXO-positive individuals (53.1% with SCZ) showed no significant association (p = 0.354) for SCZ-PRS and had a much lower R2 (R2 = 0.007). To account for Type-2 error in the TOXO-positive dataset, we performed a random sampling of the TOXO-negative subpopulation (n = 130, repeated 100 times) to simulate equivalent power between groups: the p-value was <0.05 for SCZ-PRS 55% of the time but was rarely (6% of the time) comparable to the high p-value of the seropositive group at p > 0.354. We found intriguing evidence that the SCZ-PRS predicts SCZ in TOXO-negative subjects, as expected, but not in the TOXO-positive individuals. This result highlights the importance of considering environmental risk factors to distinguish a subgroup with independent or different genetic components involved in the development of SCZ.

Association of HLA locus alleles with posttraumatic stress disorder.

BACKGROUND: Immune dysregulation has been widely observed in those with posttraumatic stress disorder (PTSD). An individual's immune response is shaped, in part, by the highly polymorphic Human Leukocyte Antigen (HLA) locus that is associated with major psychiatric disorders such as schizophrenia, major depression and bipolar disorder. The aim of the current study was to investigate the association between common HLA alleles and PTSD. METHODS: Genome-wide association data was used to predict alleles of 7 classical polymorphic HLA genes (A, B, C, DRB1, DQA1, DQB1, DPB1) in 403 lifetime PTSD cases and 369 trauma exposed controls of African ancestry. Association of HLA allelic variations with lifetime PTSD was analyzed using logistic regression, controlling for ancestry, sex and multiple comparisons. The effect of HLA alleles on gene expression was assessed by weighted correlation network analysis (WGCNA), using 353 subjects with available expression data. Enrichment analysis was performed using anRichment to identify associated pathways of each module. RESULTS: HLA-B*58:01 (p = 0.035), HLA-C*07:01 (p = 0.035), HLA-DQA1*01:01 (p = 0.003), HLA-DQB1*05:01 (p = 0.009) and HLA-DPB1*17:01 (p = 0.017) were more common in PTSD cases, while HLA-A*02:01 (p = 0.026), HLA-DQA1*05:05 (p = 0.011) and HLA-DRB1*11:01 (p < 0.001) were more frequent in controls. WGCNA was used to explore expression patterns of the PTSD related alleles. Gene expression modules of PTSD-related HLA alleles were enriched in various pathways, including pathways related to immune and neural activity. CONCLUSIONS: To the best of our knowledge, this is the first study to report an association of HLA alleles with PTSD. Altogether, our results support the link between the immune system, brain and PTSD.

Methylomic profiles reveal sex-specific differences in leukocyte composition associated with post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a debilitating mental disorder precipitated by trauma exposure. However, only some persons exposed to trauma develop PTSD. There are sex differences in risk; twice as many women as men develop a lifetime diagnosis of PTSD. Methylomic profiles derived from peripheral blood are well-suited for investigating PTSD because DNA methylation (DNAm) encodes individual response to trauma and may play a key role in the immune dysregulation characteristic of PTSD pathophysiology. In the current study, we leveraged recent methodological advances to investigate sex-specific differences in DNAm-based leukocyte composition that are associated with lifetime PTSD. We estimated leukocyte composition on a combined methylation array dataset (483 participants, ∼450 k CpG sites) consisting of two civilian cohorts, the Detroit Neighborhood Health Study and Grady Trauma Project. Sex-stratified Mann-Whitney U test and two-way ANCOVA revealed that lifetime PTSD was associated with significantly higher monocyte proportions in males, but not in females (Holm-adjusted p-val < 0.05). No difference in monocyte proportions was observed between current and remitted PTSD cases in males, suggesting that this sex-specific difference may reflect a long-standing trait of lifetime history of PTSD, rather than current state of PTSD. Associations with lifetime PTSD or PTSD status were not observed in any other leukocyte subtype and our finding in monocytes was confirmed using cell estimates based on a different deconvolution algorithm, suggesting that our sex-specific findings are robust across cell estimation approaches. Overall, our main finding of elevated monocyte proportions in males, but not in females with lifetime history of PTSD provides evidence for a sex-specific difference in peripheral blood leukocyte composition that is detectable in methylomic profiles and that may reflect long-standing changes associated with PTSD diagnosis.

Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response.

Cannabis use is increasing in the United States, as are its adverse effects. We investigated the genetics of an adverse consequence of cannabis use: cannabis-related aggression (CRA) using a genome-wide association study (GWAS) design. Our GWAS sample included 3269 African Americans (AAs) and 2546 European Americans (EAs). An additional 89 AA subjects from the Grady Trauma Project (GTP) were also examined using a proxy-phenotype replication approach. We identified genome-wide significant risk loci contributing to CRA in AAs at the serotonin receptor 2B receptor gene (HTR2B), and the lead SNP, HTR2B*rs17440378, showed nominal association to aggression in the GTP cohort of cannabis-exposed subjects. A priori evidence linked HTR2B to impulsivity/aggression but not to cannabis response. Human functional data regarding the HTR2B variant further supported our finding. Treating an Htr2b-/- knockout mouse with THC resulted in increased aggressive behavior, whereas wild-type mice following THC administration showed decreased aggression in the resident-intruder paradigm, demonstrating that HTR2B variation moderates the effects of cannabis on aggression. These concordant findings in mice and humans implicate HTR2B as a major locus associated with cannabis-induced aggression.

Response rate profiles for major depressive disorder: Characterizing early response and longitudinal nonresponse.

BACKGROUND: Definition of response is critical when seeking to establish valid predictors of treatment success. However, response at the end of study or endpoint only provides one view of the overall clinical picture that is relevant in testing for predictors. The current study employed a classification technique designed to group subjects based on their rate of change over time, while simultaneously addressing the issue of controlling for baseline severity. METHODS: A set of latent class trajectory analyses, incorporating baseline level of symptoms, were performed on a sample of 344 depressed patients from a clinical trial evaluating the efficacy of cognitive behavior therapy and two antidepressant medications (escitalopram and duloxetine) in patients with major depressive disorder. RESULTS: Although very few demographic and illness-related features were associated with response rate profiles, the aggregated effect of candidate genetic variants previously identified in large pharmacogenetic studies and meta-analyses showed a significant association with early remission as well as nonresponse. These same genetic scores showed a less compelling relationship with endpoint response categories. In addition, consistent nonresponse throughout the study treatment period was shown to occur in different subjects than endpoint nonresponse, which was verified by follow-up augmentation treatment outcomes. CONCLUSIONS: When defining groups based on the rate of change, controlling for baseline depression severity may help to identify the clinically relevant distinctions of early response on one end and consistent nonresponse on the other.

Preliminary evidence that androgen signaling is correlated with men's everyday language.

OBJECTIVES: Testosterone (T) has an integral, albeit complex, relationship with social behavior, especially in the domains of aggression and competition. However, examining this relationship in humans is challenging given the often covert and subtle nature of human aggression and status-seeking. The present study aimed to investigate whether T levels and genetic polymorphisms in the AR gene are associated with social behavior assessed via natural language use. METHODS: We used unobtrusive, behavioral, real-world ambulatory assessments of men in partnered heterosexual relationships to examine the relationship between plasma T levels, variation in the androgen receptor (AR) gene, and spontaneous, everyday language in three interpersonal contexts: with romantic partners, with co-workers, and with their children. RESULTS: Men's T levels were positively correlated with their use of achievement words with their children, and the number of AR CAG trinucleotide repeats was inversely correlated with their use of anger and reward words with their children. T levels were positively correlated with sexual language and with use of swear words in the presence of their partner, but not in the presence of co-workers or children. CONCLUSIONS: Together, these results suggest that T may influence social behavior by increasing the frequency of words related to aggression, sexuality, and status, and that it may alter the quality of interactions with an intimate partner by amplifying emotions via swearing.

Problematic alcohol use associates with sodium channel and clathrin linker 1 (SCLT1) in trauma-exposed populations.

Excessive alcohol use is extremely prevalent in the United States, particularly among trauma-exposed individuals. While several studies have examined genetic influences on alcohol use and related problems, this has not been studied in the context of trauma-exposed populations. We report results from a genome-wide association study of alcohol consumption and associated problems as measured by the alcohol use disorders identification test (AUDIT) in a trauma-exposed cohort. Results indicate a genome-wide significant association between total AUDIT score and rs1433375 [N = 1036, P = 2.61 × 10-8 (dominant model), P = 7.76 × 10-8 (additive model)], an intergenic single-nucleotide polymorphism located 323 kb upstream of the sodium channel and clathrin linker 1 (SCLT1) at 4q28. rs1433375 was also significant in a meta-analysis of two similar, but independent, cohorts (N = 1394, P = 0.0004), the Marine Resiliency Study and Systems Biology PTSD Biomarkers Consortium. Functional analysis indicated that rs1433375 was associated with SCLT1 gene expression and cortical-cerebellar functional connectivity measured via resting state functional magnetic resonance imaging. Together, findings suggest a role for sodium channel regulation and cerebellar functioning in alcohol use behavior. Identifying mechanisms underlying risk for problematic alcohol use in trauma-exposed populations is critical for future treatment and prevention efforts.

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

Genetic risk for hospitalization of African American patients with severe mental illness reveals HLA loci.

Background: Mood disorders such as major depressive and bipolar disorders, along with posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and other psychotic disorders, constitute serious mental illnesses (SMI) and often lead to inpatient psychiatric care for adults. Risk factors associated with increased hospitalization rate in SMI (H-SMI) are largely unknown but likely involve a combination of genetic, environmental, and socio-behavioral factors. We performed a genome-wide association study in an African American cohort to identify possible genes associated with hospitalization due to SMI (H-SMI). Methods: Patients hospitalized for psychiatric disorders (H-SMI; n=690) were compared with demographically matched controls (n=4467). Quality control and imputation of genome-wide data were performed following the Psychiatric Genetic Consortium (PGC)-PTSD guidelines. Imputation of the Human Leukocyte Antigen (HLA) locus was performed using the HIBAG package. Results: Genome-wide association analysis revealed a genome-wide significant association at 6p22.1 locus in the ubiquitin D (UBD/FAT10) gene (rs362514, p=9.43x10-9) and around the HLA locus. Heritability of H-SMI (14.6%) was comparable to other psychiatric disorders (4% to 45%). We observed a nominally significant association with 2 HLA alleles: HLA-A*23:01 (OR=1.04, p=2.3x10-3) and HLA-C*06:02 (OR=1.04, p=1.5x10-3). Two other genes (VSP13D and TSPAN9), possibly associated with immune response, were found to be associated with H-SMI using gene-based analyses. Conclusion: We observed a strong association between H-SMI and a locus that has been consistently and strongly associated with SCZ in multiple studies (6p21.32-p22.1), possibly indicating an involvement of the immune system and the immune response in the development of severe transdiagnostic SMI.

Racial Discrimination, Neural Connectivity, and Epigenetic Aging Among Black Women.

Importance: Racial discrimination increases the risk of adverse brain health outcomes, potentially via neuroplastic changes in emotion processing networks. The involvement of deep brain regions (brainstem and midbrain) in these responses is unknown. Potential associations of racial discrimination with alterations in deep brain functional connectivity and accelerated epigenetic aging, a process that substantially increases vulnerability to health problems, are also unknown. Objective: To examine associations of racial discrimination with brainstem and midbrain resting-state functional connectivity (RSFC) and DNA methylation age acceleration (DMAA) among Black women in the US. Design, Setting, and Participants: This cohort study was conducted between January 1, 2012, and February 28, 2015, and included a community-based sample of Black women (aged ≥18 years) recruited as part of the Grady Trauma Project. Self-reported racial discrimination was examined in association with seed-to-voxel brain connectivity, including the locus coeruleus (LC), periaqueductal gray (PAG), and superior colliculus (SC); an index of DMAA (Horvath clock) was also evaluated. Posttraumatic stress disorder (PTSD), trauma exposure, and age were used as covariates in statistical models to isolate racial discrimination-related variance. Data analysis was conducted between January 10 and October 30, 2023. Exposure: Varying levels of racial discrimination exposure, other trauma exposure, and posttraumatic stress disorder (PTSD). Main Outcomes and Measures: Racial discrimination frequency was assessed with the Experiences of Discrimination Scale, other trauma exposure was evaluated with the Traumatic Events Inventory, and current PTSD was evaluated with the PTSD Symptom Scale. Seed-to-voxel functional connectivity analyses were conducted with LC, PAG, and SC seeds. To assess DMAA, the Methylation EPIC BeadChip assay (Illumina) was conducted with whole-blood samples from a subset of 49 participants. Results: This study included 90 Black women, with a mean (SD) age of 38.5 (11.3) years. Greater racial discrimination was associated with greater left LC RSFC to the bilateral precuneus (a region within the default mode network implicated in rumination and reliving of past events; cluster size k = 228; t85 = 4.78; P < .001, false discovery rate-corrected). Significant indirect effects were observed for the left LC-precuneus RSFC on the association between racial discrimination and DMAA (ß [SE] = 0.45 [0.16]; 95% CI, 0.12-0.77). Conclusions and Relevance: In this study, more frequent racial discrimination was associated with proportionately greater RSFC of the LC to the precuneus, and these connectivity alterations were associated with DMAA. These findings suggest that racial discrimination contributes to accelerated biological aging via altered connectivity between the LC and default mode network, increasing vulnerability for brain health problems.