Interrogation of human hematopoiesis at single-cell and single-variant resolution

Ulirsch, Jacob C.; Lareau, Caleb A.; Bao, Erik L.; Ludwig, Leif S.; Guo, Michael H.; Benner, Christian; Satpathy, Ansuman T.; Kartha, Vinay K.; Salem, Rany M.; Hirschhorn, Joel N.; Finucane, Hilary; Aryee, Martin J.; Buenrostro, Jason D.; Sankaran, Vijay G.

doi:10.1038/s41588-019-0362-6

Cited by 175 publications

(313 citation statements)

References 73 publications

(97 reference statements)

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“…Only 39% of the 2,225 PIP>0.95 SNPs were also lead GWAS SNPs (defined as MAF>0.001 SNPs with P<5×10 -8 and no MAF>0.001 SNP with a smaller p-value within 1Mb) ( Supplementary Table 7), demonstrating the importance of using fine-mapped SNPs rather than lead GWAS SNPs for downstream analysis. 31% of the PIP>0.95 SNPs resided in coding regions and 22% were non-synonymous (broadly consistent with previous fine-mapping studies 8,12 ) (Supplementary Table 7). When restricting the analysis to 15 genetically uncorrelated traits (|rg|<0.2; Methods and Supplementary Tables 8-9) we identified 1,626 PIP>0.95 SNP-trait pairs spanning 1,496 unique SNPs, with a median distance of 9kb between a PIP>0.95 SNP and the nearest lead GWAS SNP for the same trait (Supplementary Table 7).…”

Section: Functionally Informed Fine-mapping Of 47 Complex Traits In Tsupporting

confidence: 87%

“…Details of the PolyFun method are provided in the Methods section; we have released opensource software implementing PolyFun in conjunction with SuSiE 22 and FINEMAP 23 (see URLs). In all analyses in this manuscript, we applied PolyFun using summary LD information estimated directly from the target samples (both for running S-LDSC and for running SuSiE or FINEMAP), as previously recommended for fine-mapping methods 12,30 .…”

Section: (See Methods)mentioning

confidence: 99%

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Functionally-informed fine-mapping and polygenic localization of complex trait heritability

Weissbrod

Hormozdiari

Benner

et al. 2019

Preprint

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162

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Fine-mapping aims to identify causal variants impacting complex traits. Several recent methods improve fine-mapping accuracy by prioritizing variants in enriched functional annotations. However, these methods can only use information at genome-wide significant loci (and/or a small number of functional annotations), severely limiting the benefit of functional data. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy using genome-wide functional data for a broad set of coding, conserved, regulatory and LD-related annotations. PolyFun prioritizes variants in enriched functional annotations by specifying prior causal probabilities for fine-mapping methods such as SuSiE or FINEMAP, employing special procedures to ensure robustness to model misspecification and winner's curse. In simulations, PolyFun + SuSiE and PolyFun + FINEMAP were well-calibrated and identified >20% more variants with posterior causal probability >0.95 than their non-functionally informed counterparts (and >33% more fine-mapped variants than previous functionally-informed fine-mapping methods). In analyses of 47 UK Biobank traits (average N=317K), PolyFun + SuSiE identified 3,025 fine-mapped varianttrait pairs with posterior causal probability >0.95, a >32% improvement vs. SuSiE; 223 variants were finemapped for multiple genetically uncorrelated traits, indicating pervasive pleiotropy. We used posterior mean per-SNP heritabilities from PolyFun + SuSiE to perform polygenic localization, constructing minimal sets of common SNPs causally explaining 50% of common SNP heritability; these sets ranged in size from 25 (hair color) to 3,400 (height) to 550,000 (chronotype). In conclusion, PolyFun prioritizes variants for functional follow-up and provides insights into complex trait architectures.

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Section: Functionally Informed Fine-mapping Of 47 Complex Traits In Tsupporting

confidence: 87%

Section: (See Methods)mentioning

confidence: 99%

Functionally-informed fine-mapping and polygenic localization of complex trait heritability

Weissbrod

Hormozdiari

Benner

et al. 2019

Preprint

Self Cite

162

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“…[6][7][8] In addition, common genetic variants in GFI1B have been associated with variation in platelet and other blood cell counts. 2,9 Notably, the C168F GFI1B variant identified in our patient has been recently found to segregate in an autosomal dominant manner in three unrelated families with mild to moderate macrothrombocytopenia, but without significant bruising or bleeding symptoms. 10,11 Comparison of affected and unaffected relatives within each family suggests that the C168F mutation is associated with a decrease in platelet counts without signs of -granule deficiency, in contrast to other GFI1B mutations that result in changes in platelet granules.…”

Section: The C168f Variant In Gfi1bmentioning

confidence: 57%

“…Given these findings, we decided to examine this variant within a large population‐based study, the UK Biobank . Within the UK Biobank, this variant has an allele frequency of 0.005487263 in individuals with South Asian ancestry.…”

Section: Resultsmentioning

confidence: 99%

“…11,13 Given these findings, we decided to examine this variant within a large population-based study, the UK Biobank. 9,16 Within the UK Biobank, this variant has an allele frequency of 0.005487263 in individuals with South Asian ancestry. We assessed the associations between the genotype of this variant and 20 blood parameters in 7628 individuals with South Asian ancestry using linear regression with covariates of age, sex, and the top 10 principal components to control for population stratification.…”

Section: The C168f Variant In Gfi1bmentioning

confidence: 99%

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Macrothrombocytopenia associated with a rare GFI1B missense variant confounding the presentation of immune thrombocytopenia

Cheng

Bao

Fiorini

et al. 2019

Pediatric Blood & Cancer

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Growth factor‐independent 1B (GFI1B) variants are a rare cause of thrombocytopenia. We report on a male child who was initially diagnosed with immune thrombocytopenia. However, subtle clinical signs led to suspicion of a genetic cause of thrombocytopenia. Gene panel sequencing revealed a rare variant in GFI1B (C168F), which has recently been reported in several families with thrombocytopenia. We demonstrate that this variant significantly alters platelet parameters in population studies. This case highlights how diagnoses of exclusion, such as immune thrombocytopenia, can be confounded by genetic variation. Our understanding of blood disorders will undoubtedly evolve from an increased knowledge of human genetic variation.

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Recent advances in the pathophysiology of PIEZO1‐related hereditary xerocytosis

et al. 2021

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Hereditary xerocytosis is a rare red blood cell disease related to gain-of-function mutations in the FAM38A gene, encoding PIEZO1, in 90% of cases; PIEZO1 is a broadly expressed mechano-transducer that plays a major role in many cell systems and tissues that respond to mechanical stress. In erythrocytes, PIEZO1 adapts the intracellular ionic content and cell hydration status to the mechanical constraints induced by the environment. Until recently, the pathophysiology of hereditary xerocytosis was mainly believed to be based on the "PIEZO1-Gardos channel axis" in erythrocytes, according to which PIEZO1-activating mutations induce a calcium influx that secondarily activates the Gardos channel, leading to potassium and water efflux and subsequently to red blood cell dehydration. However, recent studies have demonstrated additional roles for PIEZO1 during early erythropoiesis and reticulocyte maturation, as well as roles in other tissues and cells such as lymphatic vessels, hepatocytes, macrophages and platelets that may affect the pathophysiology of the disease. These findings, presented and discussed in this review, broaden our understanding of hereditary xerocytosis beyond that of primarily being a red blood cell disease and identify potential therapeutic targets. | INTRODUCTIONThe PIEZO proteins are a family of mechano-transducers first described in a neuron derived cell line in 2010. 1 The two members are PIEZO1, encoded by FAM38A on chromosome 16, and PIEZO2, encoded by FAM38B on chromosome 18. They are expressed in many tissues. 1,2 The structure of PIEZO1 has been recently elucidated. A first description of the murine protein revealed its three-dimensional structure, consisting of a three-bladed homotrimeric transmembrane helix completed by an extracellular cap. An intra-cytoplasmic domain, split into three parts, called "beams," extends from the transmembrane domain. The C-terminal end of each monomer has an extracellular domain (ECD), which forms the cap, and an intracellular domain (CTD), which appears to be connected to the paddles by the beams and closes the inner ion pore (Figure 1). The assembly provides a hydrophilic central transmembrane duct bordered by six helices that allows the passage of ions. Thus PIEZO1 constitutes a mechanosensitive ion channel due to the flexibility of the three blades. 1 Deformation of the plasma membrane subsequent to mechanical stimulation induces rotation of the PIEZO1 blades, transmitting such deformation to the ECD and CTD domains, allowing the ion channel to open using a lever-like mechanism. 2 When a compressive force is applied parallel to the axis of the ion channel, it induces lateral membrane tension, resulting in flattening and widening of PIEZO1, which causes the pore to open and allows the passage of ions. Such deformations are reversible, and PIEZO1 returns rapidly to its original conformation. [3][4][5] After opening, PIEZO1 acts as a passive channel for mono/divalent cations depending on their extracellular-intracellular Nicolas Jankovsky and Alexis Caulier...

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Interrogation of human hematopoiesis at single-cell and single-variant resolution

Cited by 175 publications

References 73 publications

Functionally-informed fine-mapping and polygenic localization of complex trait heritability

Functionally-informed fine-mapping and polygenic localization of complex trait heritability

Macrothrombocytopenia associated with a rare GFI1B missense variant confounding the presentation of immune thrombocytopenia

Recent advances in the pathophysiology of PIEZO1‐related hereditary xerocytosis

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