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Cheng, I.

Publications and source records attributed to Cheng, I..

10 recordsLinked to original sources

The Hidden Landscape of Missed Effects in Human Functional Neuroimaging

Functional neuroimaging aims to uncover brain processes underlying behavior and disease, yet studies are often underpowered to detect these effects. How this literature has shaped our understanding of brain function remains unknown, and little guidance exists for planning better powered studies. An underappreciated barrier is that commonly reported effect sizes across the brain are inflated, biasing study planning. Here, we introduce a correction for this inflation bias and show how more accurate studies can be planned using corrected effect size benchmarks from a mega-analysis of 63 typical studies across seven large datasets (52,979 participants). We find that common methods of planning studies based on uncorrected effects lead to roughly half the expected detections at typical sample sizes, with limited spatial overlap with original findings. These missed effects collectively explain meaningful additional variance in the desired outcome. We show how to recover missed effects by planning not only for power but also for a target number of detections via corrected benchmarks, or by taking a whole-brain approach with multivariate effects that individual research groups can detect (n < 50 compared to n > 1,000 for a typical univariate effect). These findings lay the groundwork for more informed study planning and a richer understanding of the widespread nature of brain effects, with implications for shared challenges (and solutions) across biomedicine.

neuroscience↗

Epigenetic remodeling and 3D chromatin reorganization governed by NKX2-1 drive neuroendocrine prostate cancer

A significant number of castration-resistant prostate cancer (CRPC) evolve into a neuroendocrine (NE) subtype termed NEPC, leading to resistance to androgen receptor (AR) pathway inhibitors and poor clinical outcomes. Through Hi-C analyses of a panel of patient-derived xenograft tumors, here we report drastically different 3D chromatin architectures between NEPC and CRPC samples. Such chromatin re-organization was faithfully recapitulated in vitro on isogenic cells undergoing NE transformation (NET). Mechanistically, neural transcription factor (TF) NKX2-1 is selectively and highly expressed in NEPC tumors and is indispensable for NET across various models. NKX2-1 preferentially binds to gene promoters, but it interacts with chromatin-pioneering factors such as FOXA2 at enhancer elements through chromatin looping, further strengthening FOXA2 binding at NE enhancers. Conversely, FOXA2 mediates regional DNA demethylation, attributing to NE enhancer priming and inducing NKX2-1 expression, forming a feed-forward loop. Single-cell multiome analyses of isogenic cells over time-course NET cells identify individual cells amid luminal-to-NE transformation, exhibiting intermediate epigenetic and transcriptome states. Lastly, NKX2-1/FOXA2 interacts with, and recruits CBP/p300 proteins to activate NE enhancers, and pharmacological inhibitors of CBP/p300 effectively blunted NE gene expression and abolished NEPC tumor growth. Thus, our study reports a hierarchical network of TFs governed by NKX2-1 in regulating the 2D and 3D chromatin re-organization during NET and uncovers a promising therapeutic approach to eradicate NEPC.

cancer biology↗

A developmental atlas of the mouse brain by single-cell mass cytometry

Development of the mammalian brain requires precisely controlled differentiation of neurons, glia, and nonneural cells. To investigate protein-level changes in these diverse cell types and their progenitors, we performed single-cell mass cytometry on whole brain (E11.5/E12.5) and microdissected telencephalon, diencephalon, mesencephalon, and rhombencephalon (E13.5-P4) collected at daily timepoints from C57/BL6 mice. Measuring 24,290,787 cells from 112 sample replicates with a 40-antibody panel, we quantified 85 molecularly distinct cell populations across embryonic and postnatal development, including microglia putatively phagocytosing neurites, neural cells, and myelin. Differentiation trajectory analysis also identified two separate pathways for producing oligodendrocyte precursor cells. Comparison with previous studies revealed considerable discrepancies between protein and mRNA abundances in the developing brain, demonstrating the value of protein-level measurements for identifying functional cell states. Overall, our findings demonstrate the utility of mass cytometry as a high-throughput, scalable platform for single-cell profiling of brain tissue.

neuroscience↗

A developmental atlas of somatosensory diversification and maturation in the dorsal root ganglia by single-cell mass cytometry

Precisely controlled development of the somatosensory system is essential for detecting pain, itch, temperature, mechanical touch, and body position. To investigate the protein-level changes that occur during somatosensory development, we performed single-cell mass cytometry on dorsal root ganglia from C57/BL6 mice, with litter replicates collected daily from E11.5 to P4. Measuring nearly 3 million cells, we quantified 30 molecularly distinct somatosensory glial and 41 distinct neuronal states across all time points. Analysis of differentiation trajectories revealed rare cells that coexpress two or more Trk receptors and overexpress stem cell markers, suggesting that these neurotrophic factor receptors play a role in cell fate specification. Comparison to previous RNA-based studies identified substantial differences between many protein/mRNA pairs, demonstrating the importance of protein-level measurements to identify functional cell states. Overall, this study demonstrates that mass cytometry is a high-throughput, scalable platform to rapidly phenotype somatosensory tissues.

neuroscience↗

Genome-wide Association Study of Pancreatic Fat: The Multiethnic Cohort Adiposity Phenotype Study

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also suggestively associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUT, and rs79967607 is in intron 1 of EPM2A. PLUT, a linkRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

cell biology↗

The impact of global and local Polynesian genetic ancestry on complex traits in Native Hawaiians

Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular diseases and several common cancers have revealed an increased risk in Native Hawaiians compared to European- or Asian-Americans living in the Hawaiian islands. However, there remains a gap in our understanding of the genetic factors that affect the health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the chromosomal and sub-chromosomal scales using genome-wide SNP array data on [~]4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic proportion of Native Hawaiian ancestry ("global ancestry," which we presumed to be Polynesian in origin), as well as this ancestral component along each chromosome ("local ancestry") and tested their respective association with binary and quantitative cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated through questionnaires, we found that per 10% increase in global Polynesian genetic ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P = 1.65 10-4) and having heart failure (P = 2.18 10-4), as well as a 0.059 s.d. increase in BMI (P = 1.04 10-10). When testing the association of local Polynesian ancestry with risk of disease or biomarkers, we identified a chr6 region associated with T2D. This association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. However, we could not replicate this finding in an independent Polynesian cohort from Samoa due to the small sample size of the replication cohort. In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D. Author SummaryNative Hawaiians are one of the fastest growing ethnic minority in the U.S., and exhibit increased risk for metabolic and cardiovascular diseases. However, they are generally understudied, especially from a genetic perspective. To fill this gap, we studied the association of Polynesian genetic ancestry, at genomic and subgenomic scale, with quantitative and binary traits in self-identified Native Hawaiians. We showed that Polynesian ancestry, which likely capture both genetic and non-genetic risk factors related to Native Hawaiian people and culture are associated with increased risk for obesity, type-2 diabetes, and heart failure. While we do not endorse utilizing genetic information to supplant current standards of defining community membership through self-identity or genealogical records, our results suggest future studies could identify population-specific genetic susceptibility factors that may be useful in suggesting underlying biological mechanisms and reducing the disparity in disease interventions in Polynesian populations.

genetics↗

Population specific reference panels are crucial for the genetic analyses of Native Hawai’ians: an example of the CREBRF locus

Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals,, further contributing to the obstacles to study these populations. Here we examined the consequences due to the lack of representation by genotyping a functionally important, Polynesian-specific variant, rs373863828, in the CREBRF gene, in a large number of self-reported Native Hawaiians (N=3,693) from the Multiethnic Cohort. We found the derived allele of rs373863828 was significantly associated with several adiposity traits with large effects (e.g. 0.214 s.d., or approximately 1.28 kg/m2, per allele, in BMI as the most significant; P = 7.5x10-5). Due to the current absence of Polynesian representation in publicly accessible reference sequences, rs373863828 or any of its proxies could not be tested through imputation using these existing resources. Moreover, the association signals at this Polynesian-specific variant could not be captured by alternative approaches, such as admixture mapping. In contrast, highly accurate imputation can be achieved even if a small number (<200) of Polynesian reference individuals were available. By constructing an internal set of Polynesian reference individuals, we were able to increase sample size for analysis up to 3,936 individuals, and improved the statistical evidence of association (e.g. p = 1.5x10-7, 3x10-6, and 1.4x10-4 for BMI, hip circumference, and T2D, respectively). Taken together, our results suggest the alarming possibility that lack of representation in reference panels would inhibit discovery of functionally important, population-specific loci such as CREBRF. Yet, they could be easily detected and prioritized with improved representation of diverse populations in sequencing studies.

genetics↗

p75NTR and DR6 regulate distinct phases of axon degeneration demarcated by spheroid rupture.

The regressive events associated with trophic deprivation are critical for sculpting a functional nervous system. After nerve growth factor withdrawal, sympathetic axons maintain their structural integrity for roughly 18 hours (latent phase) followed by a rapid and near unison disassembly of axons over the next 3 hours (catastrophic phase). Here we examine the molecular basis by which axons transition from latent to catastrophic phases of degeneration following trophic withdrawal. Prior to catastrophic degeneration, we observed an increase in intra-axonal calcium. This calcium flux is accompanied by p75 neurotrophic factor receptor (NTR)-Rho-actin dependent expansion of calcium rich axonal spheroids that eventually rupture, releasing their contents to the extracellular space. Conditioned media derived from degenerating axons is capable of hastening transition into the catastrophic phase of degeneration. We also found that death receptor 6 (DR6) but not p75NTR is required for transition into the catastrophic phase in response to conditioned media but not for the intra-axonal calcium flux, spheroid formation, or rupture that occurs toward the end of latency. Our results support the existence of an inter-axonal degenerative signal that promotes catastrophic degeneration among trophically deprived axons.

neuroscience↗

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg=0.098, p=2.3x10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg=0.137, p=2.0x10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR)=1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR=1.17, 1.01-1.35) and lung cancer in never smokers (OR=1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

genetics↗

Genetic Diversity Turns a New PAGE in Our Understanding of Complex Traits

Summary/AbstractGenome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development, and clinical guidelines. However, the dominance of European-ancestry populations in GWAS creates a biased view of the role of human variation in disease, and hinders the equitable translation of genetic associations into clinical and public health applications. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioral phenotypes in 49,839 non-European individuals. Using strategies designed for analysis of multi-ethnic and admixed populations, we confirm 574 GWAS catalog variants across these traits, and find 38 secondary signals in known loci and 27 novel loci. Our data shows strong evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts, and insights into clinical implications. We strongly advocate for continued, large genome-wide efforts in diverse populations to reduce health disparities.

genetics↗