•Assigning higher weights to rare variants improves power to detect association.•Loss of function variants should have higher weights than protein altering variants.•Annotations from prediction ...software should be used to weight protein altering variants.•Optimal weighting schemes vary between genes so there is no single best method.
Weighted burden analysis can incorporate variants with different frequencies and annotations into a combined test for association between a gene and a phenotype. However there has not been a systematic exploration of which weighting schemes provide maximum power to detect association. Here we assess different weighting schemes using a number of genes for which exome-wide evidence of association with common phenotypes was obtained in 200,000 exome-sequenced UK Biobank participants. We find that there are marked differences in optimal weighting schemes between genes, both with respect to allele frequency and to annotation, implying that there is no “one-size-fits-all” scheme which is generally optimal. It seems helpful to weight rare variants more highly than common ones, to give loss of function variants higher weights than protein-altering variants and to assign higher weights to protein-altering variants predicted to have more severe effects. However with the data currently available it does not seem possible to make more specific recommendations. This research has been conducted using the UK Biobank Resource.
Objectives: To examine changes in sleep problems over a 1.5-year period among Black or African American (AA) and White or European American (EA) college students and to consider the role of racial ...discrimination as a mediator of race differences in sleep problems over time. Method: Students attending a large, predominantly White university (N = 133, 41% AA, 57% female, mean age = 18.8, SD = .90) reported on habitual sleep characteristics and experiences of racial discrimination at baseline and follow-up assessments. A latent variable for sleep problems was assessed from reports of sleep latency, duration, efficiency, and quality. Longitudinal models were used to examine race differences in sleep problems over time and the mediating role of perceived discrimination. Covariates included age, gender, parent education, parent income, body mass index, self-rated physical health, and depressive symptoms. Each of the individual sleep measures was also examined separately, and sensitivity analyses were conducted using alternative formulations of the sleep problems measure. Results: AAs had greater increases in sleep problems than EAs. Perceived discrimination was also associated with increases in sleep problems over time and mediated racial disparities in sleep. This pattern of findings was similar when each of the sleep indicators was considered separately and held with alternative sleep problems measures. Conclusions: The findings highlight the importance of racial disparities in sleep across the college years and suggest that experiences of discrimination contribute to group disparities.
A previous study of 200,000 exome-sequenced UK Biobank participants investigating the association between rare coding variants and hyperlipidaemia had implicated four genes, LDLR, PCSK9, APOC3 and ...IFITM5, at exome-wide significance. In addition, a further 43 protein-coding genes were significant with an uncorrected p value of <0.001. Exome sequence data has become available for a further 270,000 participants and weighted burden analysis to test for association with hyperlipidaemia was carried out in this sample for the 47 genes highlighted by the previous study. There was no evidence to implicate IFITM5 but LDLR, PCSK9, APOC3, ANGPTL3, ABCG5 and NPC1L1 were all statistically significant after correction for multiple testing. These six genes were also all exome-wide significant in the combined sample of 470,000 participants. Variants impairing function of LDLR and ABCG5 were associated with increased risk whereas variants in the other genes were protective. Variant categories associated with large effect sizes are cumulatively very rare and the main benefit of this kind of study seems to be to throw light on the molecular mechanisms impacting hyperlipidaemia risk, hopefully supporting attempts to develop improved therapies.
Mental health disorders have become a global problem, garnering considerable attention. However, the root causes of deteriorating mental health remain poorly understood, with existing literature ...predominantly concentrating on socioeconomic conditions and psychological factors. This study uses multi‐linear and geographically weighted regressions (GWR) to examine the associations between built and natural environmental attributes and the prevalence of depression in US counties. The findings reveal that job sprawl and land mixed use are highly correlated with a lower risk of depression. Additionally, the presence of green spaces, especially in urban area, is associated with improved mental health. Conversely, higher concentrations of air pollutants, such as PM2.5 and CO, along with increased precipitation, are linked to elevated depression rates. When considering spatial correlation through GWR, the impact of population density and social capital on mental health displays substantial spatial heterogeneity. Further analysis, focused on two high depression risk clustering regions (northwestern and southeastern counties), reveals nuanced determinants. In northwestern counties, depression rates are more influenced by factors like precipitation and socioeconomic conditions, including unemployment and income segregation. In southeastern counties, population demographic characteristics, particularly racial composition, are associated with high depression prevalence, followed by built environment factors. Interestingly, job growth and crime rates only emerge as significant factors in the context of high depression risks in southeastern counties. This study underscores the robust linkages and spatial variations between built and natural environments and mental health, emphasizing the need for effective depression treatment to incorporate these multifaceted factors.
Plain Language Summary
This study examines the associations between built and natural environmental attributes and the prevalence of depression in US counties. The findings reveal that greater job sprawl and land mixed use are associated with lower depression prevalence. Additionally, the presence of green spaces in urban area is associated with reduced depression prevalence. Conversely, higher concentrations of air pollutants, such as PM2.5 and CO, along with increased precipitation, are linked to elevated depression rates. Associations between population density and social capital with depression prevalence display substantial spatial heterogeneity. Further analysis, focused on two high depression risk clustering regions (northwestern and southeastern counties), reveals region‐specific determinants.
Key Points
Job sprawl, land mixed use, and green space associate with lower depression risk; the roles of air pollution and precipitation are opposite
Association of population density and social capital with depression prevalence exhibit significant spatial diversity
Precipitation and socioeconomic status mainly affect northwestern counties; population demographics plays key role in southeastern counties
Interleukin-7 (IL-7) supports the growth and chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL), particularly the early T-cell precursor subtype (ETP-ALL), which frequently has activating ...mutations of IL-7 signaling. Signal transducer and activator of transcription (STAT5) is an attractive therapeutic target because it is almost universally activated in ETP-ALL, even in the absence of mutations of upstream activators such as the IL-7 receptor (IL-7R), Janus kinase, and Fms-like tyrosine kinase 3 (FLT3). To examine the role of activated STAT5 in ETP-ALL, we have used a Lmo2-transgenic (Lmo2Tg) mouse model in which we can monitor chemoresistant preleukemia stem cells (pre-LSCs) and leukemia stem cells (LSCs) that drive T-ALL development and relapse following chemotherapy. Using IL-7R-deficient Lmo2Tg mice, we show that IL-7 signaling was not required for the formation of pre-LSCs but essential for their expansion and clonal evolution into LSCs to generate T-ALL. Activated STAT5B was sufficient for the development of T-ALL in IL-7R-deficient Lmo2Tg mice, indicating that inhibition of STAT5 is required to block the supportive signals provided by IL-7. To further understand the role of activated STAT5 in LSCs of ETP-ALL, we developed a new transgenic mouse that enables T-cell specific and doxycycline-inducible expression of the constitutively activated STAT5B1∗6 mutant. Expression of STAT5B1∗6 in T cells had no effect alone but promoted expansion and chemoresistance of LSCs in Lmo2Tg mice. Pharmacologic inhibition of STAT5 with pimozide-induced differentiation and loss of LSCs, while enhancing response to chemotherapy. Furthermore, pimozide significantly reduced leukemia burden in vivo and overcame chemoresistance of patient-derived ETP-ALL xenografts. Overall, our results demonstrate that STAT5 is an attractive therapeutic target for eradicating LSCs in ETP-ALL.
This longitudinal study was based on the outcomes of Donor Lymphocyte Infusion (DLI) for falling peripheral blood (PB) CD34+ and CD3+ donor chimerism (DC).
From 2012 to 2018, data was collected from ...the BMT database and electronic medical records (EMR). The primary objective was to compare the indication for DLI based on falling PB CD34+ or CD3+ DC in patients post allo-SCT for AML and MDS and their overall survival (OS).
18/70 patients met the inclusion criteria. Indications for DLI were i) falling PB CD34+ DC ≤ 80 % with morphological relapse, ii) falling PB CD34+ DC ≤ 80 % without morphological relapse and iii) falling PB CD3+ DC ≤ 80 % without falling PB CD34+ DC. Log rank analysis showed falling PB CD34+ DC and morphological relapse had significantly lower OS. Linear regression demonstrated better OS post DLI if there was PB CD34+ and CD3+ chimerism response at 30 days (p = 0.029), GVHD (p = 0.032) and tapering immunosuppression at the time of falling DC (p = 0.042).
DLI for PB CD34+ DC values ≤ 80 % and morphological relapse had the lowest OS. In this study, full DC was achieved after DLI even with a PB CD3+DC value as low as 13 %, provided the PB CD34+ DC remained > 80 %. Further research is vital in CD34+ DC as a biomarker for disease relapse and loss of engraftment.
•Peripheral blood (PB) CD34+ and CD3+ DC measurements post allo-SCT for AML and MDS.•DLI was initiated at fall in PB DC to ≤ 80 % for CD34+ or CD3+.•PB CD34+ DC ≤ 80 % had lower OS compared to PB CD3+ DC ≤ 80 %.•Evidence of morphological relapse with PB CD34+ DC ≤ 80 % had the lowest OS.•Further research is vital in CD34+ DC to provide understanding into relapse biology.
ZEB1 and ZEB2 are structurally related E-box binding homeobox transcription factors that induce epithelial to mesenchymal transitions during development and disease. As such, they regulate cancer ...cell invasion, dissemination and metastasis of solid tumors. In addition, their expression is associated with the gain of cancer stem cell properties and resistance to therapy. Using conditional loss-of-function mice, we previously demonstrated that
also plays pivotal roles in hematopoiesis, controlling important cell fate decisions, lineage commitment and fidelity. In addition, upon Zeb2 overexpression, mice spontaneously develop immature T-cell lymphoblastic leukemia. Here we show that pre-leukemic
-overexpressing thymocytes are characterized by a differentiation delay at beta-selection due to aberrant activation of the interleukin-7 receptor signaling pathway. Notably, and in contrast to Lmo2-overexpressing thymocytes, these pre-leukemic
-overexpressing T-cell progenitors display no acquired self-renewal properties. Finally,
activation in more differentiated T-cell precursor cells can also drive malignant T-cell development, suggesting that the early T-cell differentiation delay is not essential for
-mediated leukemic transformation. Altogether, our data suggest that
and
drive malignant transformation of immature T-cell progenitors via distinct molecular mechanisms.
•The study analyses exome sequence data from nearly 6,000 subjects referred to a psychiatrist with depression or a related diagnosis.•No gene is identified in which rare, functional variants ...influence risk of psychiatric referral.•Depression genetics research seems unlikely to yield findings of clinical importance until far larger samples become available.
Depression is moderately heritable but there is no common genetic variant which has a major effect on susceptibility. It is possible that some very rare variants could have substantial effect sizes and these could be identified from exome sequence data.
Data from 50,000 exome-sequenced UK Biobank participants was analysed. Subjects were treated as cases if they had reported having seen a psychiatrist for “nerves, anxiety, tension or depression”. Gene-wise weighted burden analysis was performed to see if there were any genes or sets of genes for which there was an excess of rare, functional variants in cases.
There were 5,872 cases and 43,862 controls. There were 22,028 informative genes but no gene or gene set produced a statistically significant result after correction for multiple testing. None of the genes or gene sets with the lowest p values appeared to be a biologically plausible candidate.
The phenotype is based on self-report and the cases are likely to be somewhat heterogeneous. Likewise, it is expected that some of the subjects classed as controls will in fact have suffered from depression or some other psychiatric diagnosis. The number of cases is on the low side for a study of exome sequence data.
The results conform exactly with the expectation under the null hypothesis. It seems unlikely that depression genetics research will implicate specific genes having a substantial impact on the risk of developing psychiatric illness severe enough to merit referral to a specialist until far larger samples become available.
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