| 1. |
- Repetto, Linda, et al.
(author)
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Genetic mechanisms of 184 neuro-related proteins in human plasma.
- 2023
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In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Journal article (other academic/artistic)abstract
- Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.
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| 2. |
- Repetto, Linda, et al.
(author)
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Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.
- 2023
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In: Nature Portfolio. - : Research Square Platform LLC.
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Journal article (other academic/artistic)abstract
- Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.
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| 3. |
- Broadaway, K Alaine, et al.
(author)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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In: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Journal article (peer-reviewed)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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| 4. |
- Carland, Corinne, et al.
(author)
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Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases
- 2023
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In: Clinical Proteomics. - : BMC. - 1542-6416 .- 1559-0275. ; 20:1
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Journal article (peer-reviewed)abstract
- Background: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance.Methods: We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins.Results: We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F).Conclusion: Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.
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| 5. |
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| 6. |
- Goobar, Ariel, 1962-, et al.
(author)
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Uncovering a population of gravitational lens galaxies with magnified standard candle SN Zwicky
- 2023
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In: Nature Astronomy. - 2397-3366. ; 7:9, s. 1098-1107
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Journal article (peer-reviewed)abstract
- Detecting gravitationally lensed supernovae is among the biggest challenges in astronomy. It involves a combination of two very rare phenomena: catching the transient signal of a stellar explosion in a distant galaxy and observing it through a nearly perfectly aligned foreground galaxy that deflects light towards the observer. Here we describe how high-cadence optical observations with the Zwicky Transient Facility, with its unparalleled large field of view, led to the detection of a multiply imaged type Ia supernova, SN Zwicky, also known as SN 2022qmx. Magnified nearly 25-fold, the system was found thanks to the standard candle nature of type Ia supernovae. High-spatial-resolution imaging with the Keck telescope resolved four images of the supernova with very small angular separation, corresponding to an Einstein radius of only θE = 0.167″ and almost identical arrival times. The small θE and faintness of the lensing galaxy are very unusual, highlighting the importance of supernovae to fully characterize the properties of galaxy-scale gravitational lenses, including the impact of galaxy substructures.
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| 7. |
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| 8. |
- Williamson, Alice, et al.
(author)
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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
- 2023
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
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Journal article (peer-reviewed)abstract
- Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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