cis-pQTL MR Analysis
I applied Mendelian Randomization to the asthma GWAS of Han et al.1 using cis-pQTLs from the UK Biobank Pharma Proteomics Project2 as instruments. I aimed to identify candidate proteins that may be causal in the asthma disease process.
Since each protein in the UKBB PPP has at most one cis-pQTL, I used the Wald Ratio method to estimate the causal effect of the proteins on asthma.
I used the R package TwoSampleMR.
NOTE: Because Han et al. and the UKBB PPP make use of overlapping individuals from the UK Biobank, the analysis I performed is technically one-sample-MR, not two-sample-MR. When two-sample-MR techniques are applied to a one-sample-MR scenario, inflated type 1 error can result. Thus, the standard errors and p values in the table below may be artificially small.
Results
The plot below summarizes the effect sizes and standard errors of the Bonferroni-significant proteins produced by MR analysis. Effect sizes are expressed in asthma liability units per inverse-rank-transformed protein abundance unit.
The table below provides descriptions from the UniProt database for these significant asthma-affecting proteins.
| Target UniProt | Assay Target | b | se | pval | Function [CC] |
|---|---|---|---|---|---|
| P01903 | HLA-DRA | 0.196814 | 0.0113675 | 3.7e-67 | FUNCTION: An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the beta chain HLA-DRB, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DR-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:15265931, PubMed:15322540, PubMed:17334368, PubMed:22327072, PubMed:24190431, PubMed:27591323, PubMed:29884618, PubMed:31495665, PubMed:8145819, PubMed:9075930). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819). {ECO:0000269 |
| Q01638 | IL1RL1 | -0.157073 | 0.00911024 | 1.3e-66 | FUNCTION: Receptor for interleukin-33 (IL-33) which plays crucial roles in innate and adaptive immunity, contributing to tissue homeostasis and responses to environmental stresses together with coreceptor IL1RAP (PubMed:35238669). Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. Possibly involved in helper T-cell function (Probable) (PubMed:16286016). Upon tissue injury, induces UCP2-dependent mitochondrial rewiring that attenuates the generation of reactive oxygen species and preserves the integrity of Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages (By similarity). {ECO:0000250 |
| Q15399 | TLR1 | -0.201045 | 0.0146438 | 6.8e-43 | FUNCTION: Participates in the innate immune response to microbial agents. Specifically recognizes diacylated and triacylated lipopeptides. Cooperates with TLR2 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852). Forms the activation cluster TLR2:TLR1:CD14 in response to triacylated lipopeptides, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. {ECO:0000269 |
| MICA | MICB | 0.069504 | 0.00619682 | 3.4e-29 | |
| Q15109 | AGER | -0.419182 | 0.0401882 | 1.8e-25 | FUNCTION: Cell surface pattern recognition receptor that senses endogenous stress signals with a broad ligand repertoire including advanced glycation end products, S100 proteins, high-mobility group box 1 protein/HMGB1, amyloid beta/APP oligomers, nucleic acids, histones, phospholipids and glycosaminoglycans (PubMed:27572515, PubMed:28515150, PubMed:34743181, PubMed:35974093, PubMed:24081950). Advanced glycosylation end products are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes (PubMed:21565706). These ligands accumulate at inflammatory sites during the pathogenesis of various diseases including diabetes, vascular complications, neurodegenerative disorders and cancers, and RAGE transduces their binding into pro-inflammatory responses. Upon ligand binding, uses TIRAP and MYD88 as adapters to transduce the signal ultimately leading to the induction of inflammatory cytokines IL6, IL8 and TNFalpha through activation of NF-kappa-B (PubMed:21829704, PubMed:33436632). Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key pro-inflammatory mediators (PubMed:19386136). Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling (By similarity). Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons (PubMed:19906677). ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space. Participates in endothelial albumin transcytosis together with HMGB1 through the RAGE/SRC/Caveolin-1 pathway, leading to endothelial hyperpermeability (PubMed:27572515). Mediates the loading of HMGB1 in extracellular vesicles (EVs) that shuttle HMGB1 to hepatocytes by transferrin-mediated endocytosis and subsequently promote hepatocyte pyroptosis by activating the NLRP3 inflammasome (PubMed:34743181). Binds to DNA and promotes extracellular hypomethylated DNA (CpG DNA) uptake by cells via the endosomal route to activate inflammatory responses (PubMed:24081950, PubMed:28515150). Mediates phagocytosis by non-professional phagocytes (NPP) and this is enhanced by binding to ligands including RNA, DNA, HMGB1 and histones (PubMed:35974093). Promotes NPP-mediated phagocytosis of Saccharomyces cerevisiae spores by binding to RNA attached to the spore wall (PubMed:35974093). Also promotes NPP-mediated phagocytosis of apoptotic cells (PubMed:35974093). Following DNA damage, recruited to DNA double-strand break sites where it colocalizes with the MRN repair complex via interaction with double-strand break repair protein MRE11 (By similarity). Enhances the endonuclease activity of MRE11, promoting the end resection of damaged DNA (By similarity). Promotes DNA damage repair in trophoblasts which enhances trophoblast invasion and contributes to placental development and maintenance (PubMed:33918759). Protects cells from DNA replication stress by localizing to damaged replication forks where it stabilizes the MCM2-7 complex and promotes faithful progression of the replication fork (PubMed:36807739). Mediates the production of reactive oxygen species (ROS) in human endothelial cells (PubMed:25401185). {ECO:0000250 |
| P09919 | CSF3 | 0.722037 | 0.0795319 | 1.1e-19 | FUNCTION: Granulocyte/macrophage colony-stimulating factors are cytokines that act in hematopoiesis by controlling the production, differentiation, and function of 2 related white cell populations of the blood, the granulocytes and the monocytes-macrophages. This CSF induces granulocytes. |
| Q9HB29 | IL1RL2 | -0.128852 | 0.0143347 | 2.5e-19 | FUNCTION: Receptor for interleukin-36 (IL36A, IL36B and IL36G). After binding to interleukin-36 associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex which mediates interleukin-36-dependent activation of NF-kappa-B, MAPK and other pathways (By similarity). The IL-36 signaling system is thought to be present in epithelial barriers and to take part in local inflammatory response; it is similar to the IL-1 system. Seems to be involved in skin inflammatory response by induction of the IL-23/IL-17/IL-22 pathway. {ECO:0000250 |
| P16871 | IL7R | 0.0681125 | 0.00758114 | 2.6e-19 | FUNCTION: Receptor for interleukin-7. Also acts as a receptor for thymic stromal lymphopoietin (TSLP). |
| P14778 | IL1R1 | 0.307053 | 0.035607 | 6.5e-18 | FUNCTION: Receptor for IL1A, IL1B and IL1RN (PubMed:2950091, PubMed:37315560). After binding to interleukin-1 associates with the coreceptor IL1RAP to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B, MAPK and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Binds ligands with comparable affinity and binding of antagonist IL1RN prevents association with IL1RAP to form a signaling complex. Involved in IL1B-mediated costimulation of IFNG production from T-helper 1 (Th1) cells (PubMed:10653850). {ECO:0000269 |
| Q92599 | SEPTIN8 | -0.508966 | 0.0635853 | 1.2e-15 | FUNCTION: Filament-forming cytoskeletal GTPase (By similarity). May play a role in platelet secretion (PubMed:15116257). Seems to participate in the process of SNARE complex formation in synaptic vesicles (By similarity). {ECO:0000250, ECO:0000250 |
| P13747 | HLA-E | 0.153178 | 0.0202326 | 3.70814e-14 | FUNCTION: Non-classical major histocompatibility class Ib molecule involved in immune self-nonself discrimination. In complex with B2M/beta-2-microglobulin binds nonamer self-peptides derived from the signal sequence of classical MHC class Ia molecules (VL9 peptides - VMAPRT[V/L][L/V/I/F]L) (PubMed:18083576, PubMed:18339401, PubMed:35705051, PubMed:37264229, PubMed:9754572). Peptide-bound HLA-E-B2M heterotrimeric complex primarily functions as a ligand for natural killer (NK) cell inhibitory receptor KLRD1-KLRC1, enabling NK cells to monitor the expression of other MHC class I molecules in healthy cells and to tolerate self (PubMed:17179229, PubMed:18083576, PubMed:37264229, PubMed:9486650, PubMed:9754572). Upon cellular stress, preferentially binds signal sequence-derived peptides from stress-induced chaperones and is no longer recognized by NK cell inhibitory receptor KLRD1-KLRC1, resulting in impaired protection from NK cells (PubMed:12461076). Binds signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules and acts as a ligand for NK cell activating receptor KLRD1-KLRC2, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy (PubMed:30134159, PubMed:37264229, PubMed:9754572). Besides self-peptides, can also bind and present pathogen-derived peptides conformationally similar to VL9 peptides to alpha-beta T cell receptor (TCR) on unconventional CD8-positive cytotoxic T cells, ultimately triggering antimicrobial immune response (PubMed:16474394, PubMed:20195504, PubMed:30087334, PubMed:34228645). Presents HIV gag peptides (immunodominant KAFSPEVIPMF and subdominant KALGPAATL epitopes) predominantly to CD8-positive T cell clones expressing a TRAV17-containing TCR, triggering HLA-E-restricted T cell responses (PubMed:34228645). Presents mycobacterial peptides to HLA-E-restricted CD8-positive T cells eliciting both cytotoxic and immunoregulatory functions (PubMed:20195504, PubMed:35705051). {ECO:0000269 |
| P08887 | IL6R | 0.0379751 | 0.00561936 | 1.4e-11 | FUNCTION: Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal (PubMed:28265003). Signal activation necessitate an association with IL6ST. Activation leads to the regulation of the immune response, acute-phase reactions and hematopoiesis (PubMed:30995492, PubMed:31235509). The interaction with membrane-bound IL6R and IL6ST stimulates 'classic signaling', the restricted expression of the IL6R limits classic IL6 signaling to only a few tissues such as the liver and some cells of the immune system. Whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable). {ECO:0000269 |
| Q10587 | TEF | 0.611629 | 0.096029 | 1.9e-10 | FUNCTION: Transcription factor that binds to and transactivates the TSHB promoter. Binds to a minimal DNA-binding sequence 5'-[TC][AG][AG]TTA[TC][AG]-3'. |
| P24394 | IL4R | -0.124614 | 0.020448 | 1.1e-09 | FUNCTION: Receptor for both interleukin 4 and interleukin 13 (PubMed:17030238). Couples to the JAK1/2/3-STAT6 pathway. The IL4 response is involved in promoting Th2 differentiation. The IL4/IL13 responses are involved in regulating IgE production and, chemokine and mucus production at sites of allergic inflammation. In certain cell types, can signal through activation of insulin receptor substrates, IRS1/IRS2. {ECO:0000269 |
| O95407 | TNFRSF6B | -0.127021 | 0.0211779 | 2e-09 | FUNCTION: Decoy receptor that can neutralize the cytotoxic ligands TNFS14/LIGHT, TNFSF15 and TNFSF6/FASL. Protects against apoptosis. {ECO:0000269 |
| P19075 | TSPAN8 | -0.0744569 | 0.0127618 | 5.4e-09 | FUNCTION: Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling (PubMed:27180357, PubMed:36078095). Participates thereby in diverse biological functions such as cell signal transduction, migration and protein trafficking (PubMed:25761241). Promotes ADAM17-mediated TNF-alpha processing through recruitment of ADAM17 to tetraspanin-enriched micro-domains (TEMs) (PubMed:36078095). Forms a complex with RICTOR and integrin alpha3/ITGA3 to mediate mTORC2 activation and AKT1 phosphorylation leading to cell migration (PubMed:25761241). Reduces apoptosis and autophagy induced by high glucose levels through forming a complex with mTOR and RICTOR (PubMed:35904232). Contributes to the maintenance of intestinal epithelial barrier and plays a role in the regulation of intestine inflammation by switching interferon gamma receptor 1/IFNGR1 from clathrin-dependent to lipid raft-dependent endocytosis route to limit STAT1 activation magnitude and duration (PubMed:37204469). Acts as a modulator of the endothelin axis by associating with endothelin converting enzyme ECE1 and regulating its activity of conversion of the endothelin-1 precursor to endothelin (PubMed:37835445). {ECO:0000269 |
| Q92956 | TNFRSF14 | -0.307197 | 0.0529808 | 6.7e-09 | FUNCTION: Receptor for four distinct ligands: The TNF superfamily members TNFSF14/LIGHT and homotrimeric LTA/lymphotoxin-alpha and the immunoglobulin superfamily members BTLA and CD160, altogether defining a complex stimulatory and inhibitory signaling network (PubMed:10754304, PubMed:18193050, PubMed:23761635, PubMed:9462508). Signals via the TRAF2-TRAF3 E3 ligase pathway to promote immune cell survival and differentiation (PubMed:19915044, PubMed:9153189, PubMed:9162022). Participates in bidirectional cell-cell contact signaling between antigen presenting cells and lymphocytes. In response to ligation of TNFSF14/LIGHT, delivers costimulatory signals to T cells, promoting cell proliferation and effector functions (PubMed:10754304). Interacts with CD160 on NK cells, enhancing IFNG production and anti-tumor immune response (PubMed:23761635). In the context of bacterial infection, acts as a signaling receptor on epithelial cells for CD160 from intraepithelial lymphocytes, triggering the production of antimicrobial proteins and pro-inflammatory cytokines (By similarity). Upon binding to CD160 on activated CD4+ T cells, down-regulates CD28 costimulatory signaling, restricting memory and alloantigen-specific immune response (PubMed:18193050). May interact in cis (on the same cell) or in trans (on other cells) with BTLA (By similarity) (PubMed:19915044). In cis interactions, appears to play an immune regulatory role inhibiting in trans interactions in naive T cells to maintain a resting state. In trans interactions, can predominate during adaptive immune response to provide survival signals to effector T cells (By similarity) (PubMed:19915044). {ECO:0000250 |
| O94992 | HEXIM1 | 0.506472 | 0.0886286 | 1.1e-08 | FUNCTION: Transcriptional regulator which functions as a general RNA polymerase II transcription inhibitor (PubMed:14580347, PubMed:15201869, PubMed:15713661). Core component of the 7SK RNP complex: in cooperation with 7SK snRNA sequesters P-TEFb in a large inactive 7SK snRNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation (PubMed:12832472, PubMed:14580347, PubMed:15201869, PubMed:15713661). May also regulate NF-kappa-B, ESR1, NR3C1 and CIITA-dependent transcriptional activity (PubMed:15940264, PubMed:15941832, PubMed:17088550). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728). {ECO:0000269 |
| Q7KYR7 | BTN2A1 | 0.115332 | 0.0216516 | 1e-07 | |
| Q16610 | ECM1 | 0.0481352 | 0.00922327 | 1.8e-07 | FUNCTION: Involved in endochondral bone formation as negative regulator of bone mineralization. Stimulates the proliferation of endothelial cells and promotes angiogenesis. Inhibits MMP9 proteolytic activity. {ECO:0000269 |
| P40121 | CAPG | 0.0382853 | 0.00741196 | 2.4e-07 | FUNCTION: Calcium-sensitive protein which reversibly blocks the barbed ends of actin filaments but does not sever preformed actin filaments. May play an important role in macrophage function. May play a role in regulating cytoplasmic and/or nuclear structures through potential interactions with actin. May bind DNA. |
| Q8WWN9 | IPCEF1 | -0.373547 | 0.0745375 | 5.4e-07 | FUNCTION: Enhances the promotion of guanine-nucleotide exchange by PSCD2 on ARF6 in a concentration-dependent manner. {ECO:0000250}. |
| Q9Y2W6 | TDRKH | -0.0957814 | 0.0191257 | 5.5e-07 | FUNCTION: Participates in the primary piRNA biogenesis pathway and is required during spermatogenesis to repress transposable elements and prevent their mobilization, which is essential for the germline integrity. The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. Required for the final steps of primary piRNA biogenesis by participating in the processing of 31-37 nt intermediates into mature piRNAs. May act in pi-bodies and piP-bodies by transferring piRNA precursors or intermediates to or between these granules. {ECO:0000250 |
| P78410 | BTN3A2 | -0.0469995 | 0.00939141 | 5.6e-07 | FUNCTION: Plays a role in T-cell responses in the adaptive immune response. Inhibits the release of IFNG from activated T-cells. {ECO:0000269 |
| O14618 | CCS | 0.0614329 | 0.0129239 | 2e-06 | FUNCTION: Delivers copper to copper zinc superoxide dismutase (SOD1). |
| Q16762 | TST | -0.302632 | 0.0643881 | 2.6e-06 | FUNCTION: Formation of iron-sulfur complexes, cyanide detoxification or modification of sulfur-containing enzymes. Other thiol compounds, besides cyanide, can act as sulfur ion acceptors. Also has weak mercaptopyruvate sulfurtransferase (MST) activity (By similarity). Together with MRPL18, acts as a mitochondrial import factor for the cytosolic 5S rRNA. Only the nascent unfolded cytoplasmic form is able to bind to the 5S rRNA. {ECO:0000250, ECO:0000269 |
| P20472 | PVALB | -0.0373988 | 0.00795698 | 2.6e-06 | FUNCTION: In muscle, parvalbumin is thought to be involved in relaxation after contraction (By similarity). It binds two calcium ions (PubMed:15122922, PubMed:39584689). {ECO:0000250 |
| Q5R372 | RABGAP1L | -0.446909 | 0.0972316 | 4.3e-06 | FUNCTION: GTP-hydrolysis activating protein (GAP) for small GTPase RAB22A, converting active RAB22A-GTP to the inactive form RAB22A-GDP (PubMed:16923123). Plays a role in endocytosis and intracellular protein transport. Recruited by ANK2 to phosphatidylinositol 3-phosphate (PI3P)-positive early endosomes, where it inactivates RAB22A, and promotes polarized trafficking to the leading edge of the migrating cells. Part of the ANK2/RABGAP1L complex which is required for the polarized recycling of fibronectin receptor ITGA5 ITGB1 to the plasma membrane that enables continuous directional cell migration (By similarity). {ECO:0000250 |
| P22455 | FGFR4 | 0.0302336 | 0.00659797 | 4.6e-06 | FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. {ECO:0000269 |
Interpretation of results
The top protein hits in the table above are consistent with the known biology of asthma. As would be expected for an immunologically-driven phenotype, these hits consist mostly of cytokine receptors, innate immune system pattern receptors, and components of the MHC/HLA molecule.
The direction of some of the effects is surprising: for instance, TLR1, an innate-immune system receptor, is associated with lower asthma risk. This finding may be explained by Donoghue et al.'s3 observation that TLR upregulates IL-27, an anti-inflammatory cytokine that protects against asthma.
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Yi Han, Qiong Jia, Pedram Shafiei Jahani, Benjamin P Hurrell, Calvin Pan, Pin Huang, Janet Gukasyan, Nicholas C Woodward, Eleazar Eskin, Frank D Gilliland, and others. Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma. Nature Communications, 11(1):1776, 2020. URL: https://www.nature.com/articles/s41467-020-15649-3. ↩
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Benjamin B Sun, Joshua Chiou, Matthew Traylor, Christian Benner, Yi-Hsiang Hsu, Tom G Richardson, Praveen Surendran, Anubha Mahajan, Chloe Robins, Steven G Vasquez-Grinnell, and others. Plasma proteomic associations with genetics and health in the UK Biobank. Nature, 622(7982):329–338, 2023. URL: https://www.nature.com/articles/s41586-023-06592-6. ↩
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Lauren J Donoghue, Christian Benner, Diana Chang, Flaviyan Jerome Irudayanathan, Rion K Pendergrass, Brian L Yaspan, Anubha Mahajan, and Mark I McCarthy. Integration of biobank-scale genetics and plasma proteomics reveals evidence for causal processes in asthma risk and heterogeneity. Cell Genomics, 2025. URL: https://www.cell.com/cell-genomics/fulltext/S2666-979X(25)00096-5. ↩