Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders.

Studies of the genetics of psychiatric disorders have become one of the most exciting and fast-moving areas in human genetics. A decade ago, there were few reproducible findings, and now there are hundreds. In this review, we focus on the findings that have illuminated the genetic architecture of psychiatric disorders and the challenges of using these findings to inform our understanding of pathophysiology. The evidence is now overwhelming that psychiatric disorders are "polygenic"-that many genetic loci contribute to risk. With the exception of a subset of those with ASD, few individuals with a psychiatric disorder have a single, deterministic genetic cause; rather, developing a psychiatric disorder is influenced by hundreds of different genetic variants, consistent with a polygenic model. As progressively larger studies have uncovered more about their genetic architecture, the need to elucidate additional architectures has become clear. Even if we were to have complete knowledge of the genetic architecture of a psychiatric disorder, full understanding requires deep knowledge of the functional genomic architecture-the implicated loci impact regulatory processes that influence gene expression and the functional coordination of genes that control biological processes. Following from this is cellular architecture: of all brain regions, cell types, and developmental stages, where and when are the functional architectures operative? Given that the genetic architectures of different psychiatric disorders often strongly overlap, we are challenged to re-evaluate and refine the diagnostic architectures of psychiatric disorders using fundamental genetic and neurobiological data.

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.

Common Disease Is More Complex Than Implied by the Core Gene Omnigenic Model.

The evidence that most adult-onset common diseases have a polygenic genetic architecture fully consistent with robust biological systems supported by multiple back-up mechanisms is now overwhelming. In this context, we consider the recent "omnigenic" or "core genes" model. A key assumption of the model is that there is a relatively small number of core genes relevant to any disease. While intuitively appealing, this model may underestimate the biological complexity of common disease, and therefore, the goal to discover core genes should not guide experimental design. We consider other implications of polygenicity, concluding that a focus on patient stratification is needed to achieve the goals of precision medicine.

Sufficient conditions for rapid range expansion of a boreal conifer.

Unprecedented modern rates of warming are expected to advance boreal forest into Arctic tundra1, thereby reducing albedo2-4, altering carbon cycling4 and further changing climate1-4, yet the patterns and processes of this biome shift remain unclear5. Climate warming, required for previous boreal advances6-17, is not sufficient by itself for modern range expansion of conifers forming forest-tundra ecotones5,12-15,17-20. No high-latitude population of conifers, the dominant North American Arctic treeline taxon, has previously been documented5 advancing at rates following the last glacial maximum (LGM)6-8. Here we describe a population of white spruce (Picea glauca) advancing at post-LGM rates7 across an Arctic basin distant from established treelines and provide evidence of mechanisms sustaining the advance. The population doubles each decade, with exponential radial growth in the main stems of individual trees correlating positively with July air temperature. Lateral branches in adults and terminal leaders in large juveniles grow almost twice as fast as those at established treelines. We conclude that surpassing temperature thresholds1,6-17, together with winter winds facilitating long-distance dispersal, deeper snowpack and increased soil nutrient availability promoting recruitment and growth, provides sufficient conditions for boreal forest advance. These observations enable forecast modelling with important insights into the environmental conditions converting tundra into forest.

Robust Hi-C Maps of Enhancer-Promoter Interactions Reveal the Function of Non-coding Genome in Neural Development and Diseases.

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input "easy Hi-C" protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.

mBAT-combo: A more powerful test to detect gene-trait associations from GWAS data.

Gene-based association tests aggregate multiple SNP-trait associations into sets defined by gene boundaries and are widely used in post-GWAS analysis. A common approach for gene-based tests is to combine SNPs associations by computing the sum of χ2 statistics. However, this strategy ignores the directions of SNP effects, which could result in a loss of power for SNPs with masking effects, e.g., when the product of two SNP effects and the linkage disequilibrium (LD) correlation is negative. Here, we introduce "mBAT-combo," a set-based test that is better powered than other methods to detect multi-SNP associations in the context of masking effects. We validate the method through simulations and applications to real data. We find that of 35 blood and urine biomarker traits in the UK Biobank, 34 traits show evidence for masking effects in a total of 4,273 gene-trait pairs, indicating that masking effects is common in complex traits. We further validate the improved power of our method in height, body mass index, and schizophrenia with different GWAS sample sizes and show that on average 95.7% of the genes detected only by mBAT-combo with smaller sample sizes can be identified by the single-SNP approach with a 1.7-fold increase in sample sizes. Eleven genes significant only in mBAT-combo for schizophrenia are confirmed by functionally informed fine-mapping or Mendelian randomization integrating gene expression data. The framework of mBAT-combo can be applied to any set of SNPs to refine trait-association signals hidden in genomic regions with complex LD structures.

Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation.

Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.

Estimating hepatitis C prevalence in the United States, 2017-2020.

BACKGROUND AND AIMS: The National Health and Nutrition Examination Survey (NHANES) underestimates the true prevalence of HCV infection. By accounting for populations inadequately represented in NHANES, we created 2 models to estimate the national hepatitis C prevalence among US adults during 2017-2020. APPROACH AND RESULTS: The first approach (NHANES+) replicated previous methodology by supplementing hepatitis C prevalence estimates among the US noninstitutionalized civilian population with a literature review and meta-analysis of hepatitis C prevalence among populations not included in the NHANES sampling frame. In the second approach (persons who injected drugs [PWID] adjustment), we developed a model to account for the underrepresentation of PWID in NHANES by incorporating the estimated number of adult PWID in the United States and applying PWID-specific hepatitis C prevalence estimates. Using the NHANES+ model, we estimated HCV RNA prevalence of 1.0% (95% CI: 0.5%-1.4%) among US adults in 2017-2020, corresponding to 2,463,700 (95% CI: 1,321,700-3,629,400) current HCV infections. Using the PWID adjustment model, we estimated HCV RNA prevalence of 1.6% (95% CI: 0.9%-2.2%), corresponding to 4,043,200 (95% CI: 2,401,800-5,607,100) current HCV infections. CONCLUSIONS: Despite years of an effective cure, the estimated prevalence of hepatitis C in 2017-2020 remains unchanged from 2013 to 2016 when using a comparable methodology. When accounting for increased injection drug use, the estimated prevalence of hepatitis C is substantially higher than previously reported. National action is urgently needed to expand testing, increase access to treatment, and improve surveillance, especially among medically underserved populations, to support hepatitis C elimination goals.

Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder.

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.

THUNDER: A reference-free deconvolution method to infer cell type proportions from bulk Hi-C data.

Hi-C data provide population averaged estimates of three-dimensional chromatin contacts across cell types and states in bulk samples. Effective analysis of Hi-C data entails controlling for the potential confounding factor of differential cell type proportions across heterogeneous bulk samples. We propose a novel unsupervised deconvolution method for inferring cell type composition from bulk Hi-C data, the Two-step Hi-c UNsupervised DEconvolution appRoach (THUNDER). We conducted extensive simulations to test THUNDER based on combining two published single-cell Hi-C (scHi-C) datasets. THUNDER more accurately estimates the underlying cell type proportions compared to reference-free methods (e.g., TOAST, and NMF) and is more robust than reference-dependent methods (e.g. MuSiC). We further demonstrate the practical utility of THUNDER to estimate cell type proportions and identify cell-type-specific interactions in Hi-C data from adult human cortex tissue samples. THUNDER will be a useful tool in adjusting for varying cell type composition in population samples, facilitating valid and more powerful downstream analysis such as differential chromatin organization studies. Additionally, THUNDER estimated contact profiles provide a useful exploratory framework to investigate cell-type-specificity of the chromatin interactome while experimental data is still rare.

Methylome-wide association study of early life stressors and adult mental health.

The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data were assayed at 713 522 CpG sites from 9537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes (major depressive disorder and brief resilience scale) were conducted using DNA methylation data collected from adult whole blood samples. Two genes involved with different developmental pathways (PRICKLE2, Prickle Planar Cell Polarity Protein 2 and ABI1, Abl-Interactor-1) were annotated to CpG sites associated with preterm birth (P < 1.27 × 10-9). A further two genes important to the development of sensory pathways (SOBP, Sine Oculis Binding Protein Homolog and RPGRIP1, Retinitis Pigmentosa GTPase Regulator Interacting Protein) were annotated to sites associated with low birth weight (P < 4.35 × 10-8). The examination of methylation profile scores and genes and gene-sets annotated from associated CpGs sites found no evidence of overlap between the early life environment and mental health conditions. Birth date was associated with a significant difference in estimated lymphocyte and neutrophil counts. Previous studies have shown that early life environments influence the risk of developing mental health disorders later in life; however, this study found no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.

Splenic monocytes drive pathogenic subretinal inflammation in age-related macular degeneration.

Age-related macular degeneration (AMD) is invariably associated with the chronic accumulation of activated mononuclear phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte-derived cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor (ATR1)+ splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well understood. Using acute inflammatory and well-phenotyped AMD models, we demonstrate that angiotensin II mobilizes ATR1+ splenic monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functionally from bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist and splenectomy reduces the subretinal mononuclear phagocyte accumulation and pathological choroidal neovascularization formation. In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splenectomy also inhibit the chronic retinal inflammation and associated cone degeneration that characterizes these mice. Our observation of elevated levels of plasma angiotensin II in AMD patients, suggests that similar events take place in clinical disease and argue for the therapeutic potential of ATR1 antagonists to inhibit splenic monocytes for the treatment of blinding AMD.

Pixel walking along the boreal forest-Arctic tundra ecotone: Large scale ground-truthing of satellite-derived greenness (NDVI).

In this Technical Advance, we describe a novel method to improve ecological interpretation of remotely sensed vegetation greenness measurements that involved sampling 24,395 Landsat pixels (30 m) across 639 km of Alaska's central Brooks Range. The method goes well beyond the spatial scale of traditional plot-based sampling and thereby more thoroughly relates ground-based observations to satellite measurements. Our example dataset illustrates that, along the boreal-Arctic boundary, vegetation with the greatest Landsat Normalized Difference Vegetation Index (NDVI) is taller than 1 m, woody, and deciduous; whereas vegetation with lower NDVI tends to be shorter, evergreen, or non-woody. The field methods and associated analyses advance efforts to inform satellite data with ground-based vegetation observations using field samples collected at spatial scales that closely match the resolution of remotely sensed imagery.

Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia.

Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.

Results of the multicenter early feasibility study (EFS) of the Renata Minima stent as treatment for branch pulmonary artery stenosis and coarctation of aorta in infants.

BACKGROUND: Stent implantation has become standard of care in older children and adults for treatment of branch pulmonary artery stenosis (BPAS) and coarctation aorta (CoAo). There are no stents approved or available for infants that have the potential to be dilated to adult diameters. The Minima stent was designed to fulfill this unmet need. METHODS: Multicenter, prospective, nonrandomized early feasibility study evaluating safety and effectiveness of the Minima stent for treatment of BPAS and CoAo. Primary endpoints included: (1) successful deployment across lesion, (2) stenosis relief defined by an increase in angiographic diameter of >50% and (3) freedom from stent explant, embolization or migration at 30 days and 6 months. RESULTS: Between 2/2022 and 5/2022, 10 pts underwent Minima stent implantation with a median age and weight of 9 months (4-43 months) and 7.6 kg (5.1-16.9 kg). Procedural success and predefined stenosis relief was achieved in all cases (CoAo [n = 4], BPAS [n = 6]). Adverse events occurred in 3 pts: transient diminished lower extremity pulse (n = 2), distal stent on-balloon displacement successfully managed in the catheterization suite (n = 1). There were no deaths or major adverse events. All patients were free from stent explant and migration at 30 days and 6 months with no evidence for significant restenosis at latest follow-up. CONCLUSIONS: Implantation of the Renata Minima stent was safe and effective for the treatment of BPAS and CoAo in this small cohort of infants and young children during early follow-up. Based on these early results, an expanded study with longer follow-up is warranted.

Findings from the First Year of a Federally Funded, Direct-to-Consumer HIV Self-Test Distribution Program - United States, March 2023-March 2024.

In September 2022, CDC funded a nationwide program, Together TakeMeHome (TTMH), to expand distribution of HIV self-tests (HIVSTs) directly to consumers by mail through an online ordering portal. To publicize the availability of HIVSTs to priority audiences, particularly those disproportionately affected by HIV, CDC promoted this program through established partnerships and tailored resources from its Let's Stop HIV Together social marketing campaign. The online portal launched March 14, 2023, and through March 13, 2024, distributed 443,813 tests to 219,360 persons. Among 169,623 persons who answered at least one question on a postorder questionnaire, 67.9% of respondents were from priority audiences, 24.1% had never previously received testing for HIV, and 24.8% had not received testing in the past year. Among the subset of participants who initiated a follow-up survey, 88.3% used an HIVST themselves, 27.1% gave away an HIVST, 11.7% accessed additional preventive services, and 1.9% reported a new positive HIVST result. Mailed HIVST distribution can quickly reach large numbers of persons who have never received testing for HIV or have not received testing as often as is recommended. TTMH can help to achieve the goal of diagnosing HIV as early as possible and provides a path to other HIV prevention and care services. Clinicians, community organizations, and public health officials should be aware of HIVST programs, initiate discussions about HIV testing conducted outside their clinics or offices, and initiate follow-up services for persons who report a positive or negative HIVST result.

The Health Inequality Impact of a New Cancer Therapy Given Treatment and Disease Characteristics.

OBJECTIVES: This study aimed to perform a simulation study to quantify the health inequality impact of a cancer therapy given cancer and treatment characteristics using the distributional cost-effectiveness framework. METHODS: The following factors were varied in 10 000 simulations: lifetime risk of the disease, median overall survival (OS) with standard of care (SOC), difference in OS between non-Hispanic (NH)-Black and NH-White patients (prognostic effect), treatment effect of the new therapy relative to SOC, whether the treatment effect differs between NH-Black and NH-White patients (effect modification), health utility, drug costs, and preprogression and postprogression costs. Based on these characteristics, the incremental population net health benefits were calculated for the new therapy and applied to a US distribution of quality-adjusted life expectancy at birth. The health inequality impact was quantified as the difference in the degree of inequality in the "post-new therapy" versus "pre-new therapy" quality-adjusted life expectancy distributions. RESULTS: For cancer types characterized by relatively large lifetime risk, large median OS with SOC, large treatment effect, and large effect modification, the direction of the impact of the new therapy on inequality is easy to predict. When effect modification is minor or absent, which is a realistic scenario, the direction of the inequality impact is difficult to predict. Larger incremental drug costs have a worsening effect on health inequality. CONCLUSIONS: The findings provide a guide to help decision makers and other stakeholders make an initial assessment whether a new therapy with known treatment effects for a specific tumor type can have a positive or negative health inequality impact.

Syndemic Psychosocial Conditions among Youth Living with HIV: a Latent Class Analysis.

Drug use, mental distress, and other psychosocial factors threaten HIV care for youth living with HIV (YLWH). We aimed to identify syndemic psychosocial patterns among YLWH and examine how such patterns shape HIV outcomes. Using baseline data from 208 YLWH enrolled in an HIV treatment adherence intervention, we performed latent class analysis on dichotomized responses to 9 psychosocial indicators (enacted HIV stigma; clinical depression and anxiety; alcohol, marijuana, and illicit drug misuse; food and housing insecurity; legal history). We used multinomial logistic regression to assess latent class-demographic associations and the automatic Bolck-Croon-Hagenaars method to assess HIV outcomes by class. Mean age of participants was 21 years; two thirds identified as cis male, 60% were non-Hispanic Black, and half identified as gay. Three classes emerged: "Polydrug-Socioeconomic Syndemic" (n = 29; 13.9%), "Distress-Socioeconomic Syndemic" (n = 35, 17.1%), and "Syndemic-free" (n = 142, 69.0%). Older, unemployed non-students were overrepresented in the "Polydrug-Socioeconomic Syndemic" class. Missed/no HIV care appointments was significantly higher in the "Polydrug-Socioeconomic Syndemic" class (81.4%) relative to the "Syndemic-free" (32.8%) and "Distress-Socioeconomic Syndemic" (31.0%) classes. HIV treatment nonadherence was significantly higher in the "Polydrug-Socioeconomic Syndemic" class (88.5%) relative to the "Syndemic-free" class (59.4%) but not the "Distress-Socioeconomic Syndemic" class (70.8%). Lack of HIV viral load suppression was non-significantly higher in the "Polydrug-Socioeconomic Syndemic" class (29.7%) relative to the "Syndemic-free" (16.2%) and "Distress-Socioeconomic Syndemic" (15.4%) classes. Polydrug-using, socioeconomically vulnerable YLWH are at risk for adverse HIV outcomes, warranting tailored programming integrated into extant systems of HIV care.

Adherence and persistence of HIV pre-exposure prophylaxis use in the United States.

PURPOSE: To describe medication adherence and persistence of HIV PrEP overall and compare between sex and age groups of commercially insured individuals in the United States. METHODS: We conducted a national retrospective cohort study of the Merative MarketScan Claims Database from 2011 to 2019 to describe adherence and persistence of PrEP overall and compared between sex and age groups. High adherence was defined as ≥80% of proportion of days covered and persistence was measured in days from initiation to the first day of a 60-day treatment gap. RESULTS: A total of 29 689 new PrEP users identified. Overall adherence was high (81.9%; 95% confidence interval [CI]: 81.5%-82.3%). Females were more adherent than males (adjusted odds ratio [aOR] 1.87; 95% CI: 1.50-2.34), while those ≥45-years were less adherent than individuals <45-years (aOR 0.87: 95% CI: 0.81-0.93). More than half of individuals discontinued therapy within the first year (median 238.0 days; interquartile range 99.0-507.0 days). Females were less persistent than males (hazard ratio [HR] 1.49; 95% CI: 1.34-1.65), and people ≥45-years old were more persistent (i.e., lower risk of discontinuation) than those <45-years (HR 0.43; 95% CI: 0.33-0.55). CONCLUSIONS: These findings show adherence to daily PrEP is high among commercially insured individuals but the majority still discontinue in the first year. Future research should investigate what factors influence PrEP discontinuation among this population and ways to reduce barriers to therapy maintenance to ensure the population-level benefits of PrEP treatment.

Sexual Agreement Discussions Among Adolescent Sexual Minority Men in the USA.

Nearly two-thirds of new HIV infections are attributed to primary partners, necessitating a greater understanding of relationship context of HIV transmission among sexual minority men. Sexual agreements, which are the explicit decisions couples make about sexual behaviors allowed inside and outside of their relationship, have been primarily studied among adult sexual minority men. Little work has sought to understand how adolescent sexual minority men utilize and navigate sexual agreement conversations. In this qualitative study, we explored adolescent sexual minority men's motivations for having these conversations, how they define different types of agreements (e.g., monogamous, non-monogamous), and the topics most commonly discussed in their conversations. We conducted thematic analysis of in-depth interviews with 30 partnered, HIV-negative, adolescent sexual minority men ages 15-19 years. Participants reported similar reasons, definitions, and desires for creating sexual agreements as those reported in the adult literature. Novel to this population was the influence of stigma and heterosexism on the participants' choice of sexual agreement type. Like adult sexual minority men, participants used sexual agreement conversations to respond to life events; however, the adolescents in our sample, when talking with their partners, led with the context of developmentally specific events such as leaving for college or attending a school dance. Those with more relationship experience often described having intentional, explicit sexual agreement conversations. Study findings suggest that content focused on sexual agreements is important for HIV prevention interventions designed with adolescent sexual minority men, especially young men who have less relationship experiences.