SEARCH · Search PubMed

Results for “Pleiotropy”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources

PubMed1994

The agouti gene: turned on to yellow.

The agouti locus was first identified as a result of its effects on the type and temporal deposition of coat color pigments in mammals. Many mutations at the murine agouti locus have now been found, some of which not only affect coat color, but also interfere with diverse biological processes leading to diabetes, obesity, tumor susceptibility and embryonic lethality. Correlations between the genotype and phenotype of agouti mutants, as well as reasons for the pleiotropy of effects caused by agouti mutations, have begun to unfold with the molecular cloning of the agouti gene and its surrounding genomic region.

Agouti Signaling Protein↗

PubMedDate not supplied

Geographic variations of life history strategies in Drosophila melanogaster. I. Analysis of wild-caught populations.

Life history traits--hatchability, developmental time, longevity, and egg production--of five freshly caught European populations of Drosophila melanogaster were measured under homogeneous laboratory conditions. No significant phenotypic correlations between early and late fitness could be found for the five populations at the within-population level. At the between-population level, no consistent indication of any significant genetic correlation, either positive or negative, was detected for the same traits. These results are not in agreement either with the predictions of the antagonistic pleiotropy hypothesis proposed by Williams, nor with the opposite hypothesis suggested by Lints. The results suggest that natural populations of Drosophila melanogaster are genetically different for at least some life history traits measured in the laboratory as soon as possible after capture.

Aging↗

PubMed1996

Stability of microsatellites and minisatellites in Bloom syndrome, a human syndrome of genetic instability.

Bloom syndrome (BS) is a human cancer-prone genetic disorder essentially characterized by a generalized genetic instability including a high level of sister chromatid exchanges (SCEs). Although mutator and hyper-Rec phenotypes of BS cells present analogies with those of bacteria and yeast defective in DNA mismatch repair, we report that (CA)(n) microsatellite alterations are undetectable in BS cells. Thus, our results suggest that the origin of BS mutator phenotype is not a major defect in DNA mismatch repair, allowing us to eliminate an attractive hypothesis for the pleiotropy of BS. We previously suggested that at least some of the intra-allelic rearrangements occurring in minisatellites could result from unequal SCEs. Although SCEs are abnormally frequent in BS cells, the present study failed to show any significant variation of the mutation rates of the two hypermutable minisatellites we analyzed. Thus, our results show that, in spite of an overall genetic instability, alterations in structural motifs known to be predisposed to instability by different mechanisms are undetectable in BS cells.

Bacteria↗

PubMed1995

Cytokine receptor signaling mechanisms.

Recent studies have dramatically advanced our understanding of the post-receptor signaling machinery engaged by members of the cytokine receptor superfamily. Proximal components of this signaling machinery are members of a novel class of protein tyrosine kinases termed JAKs. A working model proposes that ligand-induced dimerization of cytokine receptor subunits triggers the catalytic activation of the associated JAKs, which then couple the receptor to downstream signaling pathways. Ongoing research efforts are also yielding information regarding two potentially interactive pathways of nuclear signaling activated by cytokine receptor occupancy. These pathways are initiated by the activation of the Ras to mitogen-activated protein (MAP) kinase cascade and by the tyrosine phosphorylation of a newly defined set of transcription factors, the signal transducers and activators of transcription (STATs). Collectively, these results begin to provide a molecular basis for the long-observed phenomena of cytokine pleiotropy and redundancy.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed2026

Distinct mutational landscapes for germline and somatic cancer variants in forty tumor suppressor genes.

Germline and somatic cancer variants in tumor suppressor genes (TSGs) share loss-of-function mechanisms, but studies of a few genes (DICER1 and CEBPA) have demonstrated differences in variant consequence and location. To systematically assess whether TSGs display distinct mutational patterns, we leveraged large public genetic databases and compared 32,941 high-quality pathogenic/likely pathogenic (P/LP) germline variants in ClinVar, with 12,907 oncogenic/likely oncogenic (O/LO) somatic tumor variants from cBioPortal across 40 TSGs. Only 3,863 (9.2%) variants were shared. Eighteen TSGs showed significantly different distributions of variant occurrences by molecular consequence, replicated with non-overlapping somatic data from the COSMIC database (chi-squared tests, false discovery rate = 5%). DICER1, TP53, and SMAD4 displayed excess somatic missense events, while nine TSGs (e.g., RB1 and APC) contained excess somatic stop-gain events throughout the coding sequence. Analysis by tumor type revealed excess stop-gain events in tissues exposed to environmental mutagens with corresponding mutation signatures. For several TSGs (WT1), germline variants predispose to tumors (Wilms' tumor) distinct from the majority source of somatic data (myeloid leukemia). Germline and somatic events are also distributed unevenly across cDNA locations, with 103 regions of preferential clustering in 39 TSGs (78 somatic and 25 germline). Twenty somatic clusters contained recurring frameshifts in homopolymer runs, many in tumors with microsatellite instability. Germline clusters contain more germline-exclusive variants, some driving non-cancer phenotypes reflecting genetic pleiotropy. Altogether, germline and somatic variants of TSGs represent unique sets with substantially different patterns shaped by selection pressures from gene-specific and somatic mutational mechanisms. Characterizing these distinctions enables more accurate clinical interpretation of TSG variants.

Humans↗

PubMed2026

Microglial PICALM: A novel genetic driver and therapeutic target in vascular dementia.

BACKGROUND: Vascular dementia (VaD) lacks well-defined genetic mechanisms. Cell-type-specific effects of GWAS loci remain unexplored. METHODS: We integrated single‑cell eQTL data (183 donors, eight cell types) with VaD GWAS (3624 cases, 475,484 controls) using Mendelian randomization and Bayesian colocalization, replicated in an independent cohort (2074 cases, 456,366 controls). Subtype, snRNA‑seq, cell‑cell communication, PheWAS, expression profiling, and drug prediction with BBB permeability assessment were performed. RESULTS: Microglial PICALM was the only robustly replicated signal (OR = 0.8334, p = 5.3 × 10⁻⁴; colocalization PP.H4 > 0.75). The effect was strongest in multiple infarctions dementia (OR = 0.7746). Exploratory snRNA-seq analysis (4 VaD vs. 4 controls; GSE282111) provided supporting evidence for microglial PICALM enrichment and downregulation (p < 0.001). PICALM‑high microglia showed enhanced neurovascular‑ and phagocytosis‑related communication (e.g., SPP1, GAS6, GRN). PheWAS revealed no pleiotropy. In silico drug repurposing prioritised three FDA-approved BBB-penetrant compounds (disopyramide, benzocaine, amantadine) as candidates warranting further mechanistic validation. CONCLUSIONS: Microglial PICALM is identified as a likely genetic determinant of VaD, especially in the multiple infarctions subtype. Upregulating PICALM may be associated with a neuroprotective microglial phenotype, highlighting PICALM as a candidate therapeutic target warranting further experimental validation.

Humans↗

PubMed2004

Evidence for a gene influencing fasting LDL cholesterol and triglyceride levels on chromosome 21q.

High levels of low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol, and high levels of triglycerides (TG) are strong predictors of cardiovascular disease risk. Motivated by previous evidence for pleiotropy between cholesterol and TG levels, we conducted bivariate linkage analysis of LDL cholesterol and TG concentration among participants of the Hypertension Genetic Epidemiolgy Network (HyperGEN), one of four networks in the NHLBI sponsored Family Blood Pressure Program Project. All available hypertensive siblings and their first-degree relatives were recruited. Both phenotypes were similarly adjusted for ethnicity, study center, sex, age, age-by-sex interactions, smoking, alcohol consumption, hormone use, diabetes medication use, and waist circumference. Variance component linkage analysis was performed as implemented in SOLAR, using ethnicity-specific marker allele frequencies derived from founders and multipoint IBDs calculated in MERLIN. A maximum genome-wide empirical LOD score of 3.9 was detected on chromosome 21 at 54cM, between markers D21S2055 and D21S1446. This signal overlaps with suggestive and/or significant linkages for total cholesterol, LDL cholesterol, and apolipoprotein B in three other studies and is suggestive of one or more genes on chromosome 21q jointly regulating LDL cholesterol and TG concentration.

Aged↗

PubMed2005

Soluble osteogenic molecular signals and the induction of bone formation.

The induction of bone formation starts by erecting scaffolds of smart biomimetic matrices acting as insoluble signals affecting the release of soluble osteogenic molecular signals. The cascade of bone differentiation by induction develops as a mosaic structure singly initiated by the osteogenic proteins of the transforming growth factor-beta (TGF-beta) supergene family. The osteogenic signals when combined with an insoluble signal or substratum initiate de novo bone formation by induction and are deployed singly, synergistically and synchronously to sculpt the architecture of the mineralized bone/bone marrow organ. The osteogenic proteins of the TGF-beta superfamily are the common molecular initiators deployed for embryonic development and the induction of bone in postnatal osteogenesis, whereby molecules exploited in embryonic development are re-deployed in postnatal tissue morphogenesis as a recapitulation of embryonic development. The pleiotropy of the osteogenic proteins of the TGF-beta superfamily is highlighted by the apparent redundancy of molecular signals initiating bone formation by induction including the TGF-beta isoforms per se, powerful inducers of endochondral bone but in the primate only. Bone induction by the TGF-beta isoforms in the primate is site and tissue specific with substantial endochondral bone induction in heterotopic sites but with absent osteoinductivity in orthotopic calvarial sites on day 30 and only limited osteogenesis pericranially on day 90. Ebaf/Lefty-A, a novel member of the TGF-beta superfamily, induces chondrogenesis in calvarial defects of Papio ursinus and bone regeneration across the defect on day 30 and 90, respectively. The strikingly pleiotropic effects of the bone morphogenetic and osteogenic proteins (BMPs/OPs) spring from amino acid sequence variations in the carboxy-terminal domain and in the transduction of distinct signalling pathways by individual Smad proteins after transmembrane serine/threonine kinase complexes of type I and II receptors. Predictable bone regeneration in clinical contexts requires information concerning the expression and cross regulation of gene products of the TGF-beta superfamily. OP-1, BMP-3, TGF-beta1 and type IV collagen mRNAs expression correlates to the morphological induction and maintenance of engineered ossicles by the hOP-1 osteogenic devices in the non-human primate P. ursinus. Amino-acid sequence variations amongst BMPs/OPs in the carboxy terminal domain confer the structure/activity profile responsible for the pleiotropic activity that controls tissue induction and morphogenesis of a variety of tissues and organs by different BMPs/OPs which are helping to engineer skeletal tissue regeneration in molecular terms.

Animals↗

PubMed2004

Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid.

BACKGROUND: Monoamine neurotransmitters (serotonin, dopamine, and norepinephrine) are associated with several psychiatric disorders. Limited evidence suggests that monoamine levels are heritable, but no information concerning genetic relationships among monoamines is available. Further genetic analysis can help explain phenotypic correlations among monoamine levels and might eventually help identify genes involved in response to therapy or risk of psychopathology. METHODS: Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-hydroxy-4-methoxyphenylglycol (MHPG) were measured in cerebrospinal fluid from 271 baboons (Papio hamadryas). Variance components methods were used to estimate heritabilities, and multivariate analyses were used to estimate genetic correlations (pleiotropy) and environmental correlations between metabolites. RESULTS: Each metabolite exhibited significant heritability in baboons (5-HIAA: h(2) =.30 +/-.17; MHPG: h(2) =.36 +/-.16; HVA: h(2) =.50 +/-.19). Multivariate analyses revealed genetic correlations between 5-HIAA and HVA and between HVA and MHPG. Environmental correlations were found between 5-HIAA and HVA and between 5-HIAA and MHPG. CONCLUSIONS: Overlapping, nonidentical sets of genes influence individual variation in 5-HIAA, MHPG, and HVA levels among baboons. The phenotypic correlation between 5-HIAA and HVA observed in nonhuman primates and humans is likely due to both shared genetic and environmental factors. Genetic analyses of monoamine levels in primates can provide novel information concerning the genetics of variation among humans.

Analysis of Variance↗

PubMed2025

Alterations of gut microbiome in chronic rhinosinusitis: insights from a mendelian randomization study.

OBJECTIVE: Gut microbiome dysbiosis is associated with various diseases. Causal association between Chronic Rhinosinusitis (CRS) and gut microbiome is yet unknown. This study aimed to investigate the potential causal relationship between CRS and gut microbiome dysbiosis. METHODS: We used Genome-Wide Association Study (GWAS) data from FinnGen database for CRS. The Dutch Microbiome Project study provided data on gut microbiota species. A total of 334,182 individuals were included. Two-sample bidirectional Mendelian Randomization (MR) analysis was used to investigate causal relationship between CRS and gut microbiome. The main methods of evaluation were Inverse Variance Weighting (IVW), weighted median, weighted mode, and MR-Egger regression. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. RESULTS: Forward MR analysis indicated CRS is potentially linked to decreased risk of Haemophilus parainfluenzae (OR = 0.79, 95% CI 0.66‒0.94, p = 0.009) and increased risk of Bilophila's (OR = 1.14, 95% CI 1.02-1.27, p = 0.023) within the gut. Reduced risks in gut microbiota-related pathways like UDP-N-acetyl-d-glucosamine biosynthesis I (OR = 0.85, 95% CI 0.77‒0.94, p = 0.002) and increased risk in pathway NAD biosynthesis I from aspartate (OR = 1.14, 95% CI 1.03-1.27, p = 0.010) were also linked to CRS. Reverse MR analyses, we obtained no positive results (p > 0.05/412). CONCLUSION: This study reveals CRS exerts a causal impact on shifts within the composition of the gut microbiome and also links to the changes of gut microbiota-related metabolic pathways. The risk of changes in gut microbiota should be of greater concern in patients with CRS than in the general population. LEVEL OF EVIDENCE: Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.

Humans↗

PubMed2005

Circulating amounts of osteoprotegerin and RANK ligand: genetic influence and relationship with BMD assessed in female twins.

UNLABELLED: Osteoprotegerin (OPG) is a circulating receptor that inhibits osteoclastogenesis by binding to RANK ligand (RANKL). OPG knock-out animals develop severe osteoporosis. Treatment with OPG lowers bone resorption and increases BMD. OPG production is influenced by a wide range of hormones and cytokines. The influence of genetic factors on circulating amounts of OPG and RANKL is not known. BMD has been demonstrated to have a high heritability and there is evidence also that bone turnover and bone loss rates are controlled at least in part by genetic factors. OBJECTIVE: Assessing the genetic impact on serum OPG and RANKL in women and estimation of the relative contribution of this inheritance to the total heritability of BMD. METHODS: 188 female twins (52 DZ and 42 MZ pairs) from the Danish Twin Registry were included in the study. Mean age was 35 years (range 19-64 years), average spine BMD was 1.04 +/- 0.11 g/cm2. Serum levels of OPG and RANKL were measured by ELISA (Biomedica, Vienna, Austria). This register covers twins born in Denmark since 1870. Heritability and environmental influence was assessed using a maximum-likelihood model for genetic pleiotropy. RESULTS: RANKL levels showed a negative correlation with age and lower values in smokers. OPG levels were higher in postmenopausal women. Heritability (h(2)) was 85% for spine BMD and 52% for serum RANKL after adjustment for age, smoking and BMI. By contrast, there was no significant genetic influence on OPG levels (h(2) = 0, 95% CI: 0 to 0.31). Serum OPG was determined almost exclusively by individual environment (e(2) = 0.79), with a small, non-significant contribution from shared environment (c(2) = 0.21). Restricting analyses to the 158 premenopausal twins did not alter the findings. CONCLUSIONS: Serum OPG and RANKL levels have only a weak relation to BMD in healthy women. Phenotype correlations indicate that the genes that contribute to twin similarity for BMD are not genes regulating serum levels of RANKL or OPG. The weak correlation with BMD appears to consist in shared environmental factors.

Adult↗

PubMed2005

Antisense-mediated depletion reveals essential and specific functions of microRNAs in Drosophila development.

MicroRNAs are small noncoding RNAs that control gene function posttranscriptionally through mRNA degradation or translational inhibition. Much has been learned about the processing and mechanism of action of microRNAs, but little is known about their biological function. Here, we demonstrate that injection of 2'O-methyl antisense oligoribonucleotides into early Drosophila embryos leads to specific and efficient depletion of microRNAs and thus permits systematic loss-of-function analysis in vivo. Twenty-five of the forty-six embryonically expressed microRNAs show readily discernible defects; pleiotropy is moderate and family members display similar yet distinct phenotypes. Processes under microRNA regulation include cellularization and patterning in the blastoderm, morphogenesis, and cell survival. The largest microRNA family in Drosophila (miR-2/6/11/13/308) is required for suppressing embryonic apoptosis; this is achieved by differential posttranscriptional repression of the proapoptotic factors hid, grim, reaper, and sickle. Our findings demonstrate that microRNAs act as specific and essential regulators in a wide range of developmental processes.

Animals↗

PubMed2006

Ken & barbie selectively regulates the expression of a subset of Jak/STAT pathway target genes.

A limited number of evolutionarily conserved signal transduction pathways are repeatedly reused during development to regulate a wide range of processes. Here we describe a new negative regulator of JAK/STAT signaling and identify a potential mechanism by which the pleiotropy of responses resulting from pathway activation is generated in vivo. As part of a genetic interaction screen, we have identified Ken & Barbie (Ken) , which is an ortholog of the mammalian proto-oncogene BCL6 , as a negative regulator of the JAK/STAT pathway. Ken genetically interacts with the pathway in vivo and recognizes a DNA consensus sequence overlapping that of STAT92E in vitro. Tissue culture-based assays demonstrate the existence of Ken-sensitive and Ken-insensitive STAT92E binding sites, while ectopically expressed Ken is sufficient to downregulate a subset of JAK/STAT pathway target genes in vivo. Finally, we show that endogenous Ken specifically represses JAK/STAT-dependent expression of ventral veins lacking (vvl) in the posterior spiracles. Ken therefore represents a novel regulator of JAK/STAT signaling whose dynamic spatial and temporal expression is capable of selectively modulating the transcriptional repertoire elicited by activated STAT92E in vivo.

Animals↗

PubMed2005

Bone morphogenetic proteins in craniofacial and periodontal tissue engineering: experimental studies in the non-human primate Papio ursinus.

The bone morphogenetic and osteogenic proteins (BMPs/OPs), pleiotropic members of the transforming growth factor-beta (TGF-beta) supergene family act as soluble signals for the de novo initiation of bone formation, sculpting the multicellular mineralized structures of the bone-bone marrow organ. The strikingly pleiotropic effects of BMPs/OPs spring from amino acid sequence variations in the carboxy-terminal domain and in the transduction of distinct signalling pathways by individual Smad proteins after transmembrane serine/threonine kinase complexes of type I and II receptors. BMPs/OPs are the common molecular initiators deployed for embryonic development and the induction of bone formation and regeneration in postnatal osteogenesis. Naturally derived BMPs/OPs extracted and purified from baboon and bovine bone matrices induce complete regeneration of non-healing calvarial defects in the non-human primate Papio ursinus as well as the induction of cementogenesis and the morphogenesis of a periodontal ligament system with a faithful insertion of Sharpey's fibers into the newly formed cementum. gamma-Irradiated recombinant human osteogenic protein-1 (hOP-1) delivered by xenogeneic bovine collagenous bone matrices completely regenerated and maintained the architecture of the induced bone after treatment of calvarial defects with single applications of doses of 0.1, 0.5 and 2.5mg hOP-1 per gram of carrier matrix. The long-term implantation of hOP-1 delivered by gamma-irradiated bovine bone matrices induced the regeneration of the three essential components of the periodontium, i.e. cementum, periodontal ligament and alveolar bone. The osteogenic proteins of the TGF-beta superfamily are sculpting tissue constructs that engineer skeletal tissue regeneration in molecular terms. The pleiotropy of the signalling molecules of the TGF-beta superfamily is highlighted by the redundancy of molecular signals initiating bone formation, including the TGF-beta isoforms per se, powerful inducers of endochondral bone formation but in the primate only. The induction of bone develops a mosaic structure in which members of the TGF-beta superfamily singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis.

Animals↗

PubMed2005

FGF signaling in flies and worms: more and more relevant to vertebrate biology.

FGF signaling in the invertebrate model systems Drosophila melanogaster and Caenorhabditis elegans was initially most obviously involved in cell motility events. More recently, however, FGFs and FGF signaling in these systems have been shown to affect many additional cellular processes. This recent work has shown that the pleiotropies of these FGF receptors resemble those of their vertebrate counterparts, and, in many cases, serve as excellent models for understanding the fundamental molecular mechanisms controlling these events.

Alternative Splicing↗

PubMed2006

Zinc-binding proteins (metallothionein and alpha-2 macroglobulin) and immunosenescence.

Zinc is a relevant trace element for the efficiency of the entire immune system. The binding of zinc with some proteins, such as metallothioneins (MT) and alpha-2 macroglobulin (alpha-2M) is crucial for the immune efficiency during ageing and in age-related diseases, because these proteins may be involved in antagonistic pleiotropic effects. Indeed, the presence of chronic inflammation during ageing, generally, induces overexpression of these proteins that, due to their original biological function in fighting stressor agents, continuously sequester intracellular zinc. As a consequence, a low zinc ion availability may appear in aged organisms leading to impairments of the immune response at thymic and extrathymic levels with the risk of the appearance of age-related diseases. Therefore, MT and alpha-2M turn from protective in "young-adult age" to harmful agents in "ageing" following the basic assumption of an evolutionary theory of ageing, named the "antagonistic pleiotropy", which suggests that a trade off between early beneficial effects and late negative outcomes can occur at a genetic and molecular level. On the other hand, some polymorphisms of MT (MT2A) and alpha-2M have been associated with atherosclerosis or Alzheimer disease, respectively. Physiological zinc supplementation in elderly restores the thymic endocrine activity and innate immune response (NK cell cytotoxicity) and increases the survival rate in old mice. Therefore, zinc supplementation is useful to achieve health longevity because these zinc-binding proteins may regain their original protective task against oxidative damage with, thus, a beneficial impact on immune response.

Adult↗

PubMed2006

ARX: a gene for all seasons.

The Aristaless-related homeobox gene, ARX, is an important transcription factor with a crucial role in forebrain, pancreas and testes development. At least fifty-nine mutations have been described in the ARX gene in seven X-chromosome linked disorders involving mental retardation. Recent studies with ARX screening suggest that the gene is mutated in 9.5% of X-linked families with these disorders. Two different polyalanine expansion mutations represent 46% of all currently known mutations and show considerable pleiotropy. The ARX gene is emerging as one of the more important disease-causing genes on the X chromosome and ought to be considered for routine screening. Although the normal Arx protein is known to be a bifunctional transcriptional activator and repressor, the complete biochemical characterization of the normal and mutated ARX awaits further investigation. Pax4 was identified as one of the ARX target genes, and both proteins have crucial functions in endocrine mouse pancreas alpha-cell and beta-cell lineage specification.

Animals↗

PubMed2026

Deep learning and statistical methods identify novel asthma risk variants in Europeans.

BACKGROUND: Asthma is a common heritable respiratory disorder with a complex genetic basis. Although large-scale genome-wide association studies have identified many risk loci, the full spectrum of its polygenic architecture remains to be defined. OBJECTIVE: We refined the genetic landscape of asthma in individuals of European ancestry and improve polygenic risk prediction through statistical and deep learning-based methods. METHODS: We conducted the largest genome-wide association study meta-analysis of asthma in individuals of European ancestry, combining data from the Global Biobank Meta-analysis Initiative (121,940 cases, 1,254,131 controls) and the Million Veteran Program (36,823 cases, 398,278 controls). To enhance discovery, we applied pleiotropy-informed multitrait analysis and conditional false discovery rate approaches, each incorporating eosinophil counts as a secondary trait. In parallel, we used a Transformer-based deep learning framework to further prioritize variants and improve polygenic risk prediction. RESULTS: The meta-analysis identified 69 independent genome-wide significant loci (P < 5 × 10-8) not previously reported in asthma. Multitrait analysis of genome-wide association studies, conditional false discovery rate, and deep learning approaches uncovered additional candidate loci. Functional annotation and expression quantitative trait locus mapping implicated novel genes in immune regulation, airway remodeling, and metabolic processes. Polygenic risk score models derived from deep learning-prioritized variants outperformed those based on conventional genome-wide association study and standard statistical approaches. CONCLUSIONS: Our study yields a comprehensive map of asthma-associated loci in European ancestry populations, improves genetic risk prediction, and informs future mechanistic studies.

Humans↗