T1 Meta-analysis of idiopathic pulmonary fibrosis genome-wide analyses identifies three novel genetic signals associated with disease susceptibility
Notice bibliographique
Résumé
Introduction Idiopathic pulmonary fibrosis (IPF) is a devastating incurable lung disease. There have been three previous genome-wide association studies (GWAS) of IPF susceptibility. By combining these studies, we were able to perform the largest, densest and most powerful GWAS of IPF to date. Methods We used a two-stage approach. Stage 1 consisted of a genome-wide meta-analysis of IPF across the three previous studies. European cases and controls in each of the studies was imputed using the Haplotype Reference Consortium (HRC) reference panel. We ran genome-wide analyses adjusting for 10 principal components (to adjust for fine-scale ancestry) in each study separately and meta-analysed the results. Variants with p<5 × 10−8 in the stage 1 analysis were further analysed in two independent case-control collections (stage 2) and were defined as significantly associated with IPF risk if they were significant after multiple testing adjustments. Statistical fine-mapping and functional follow-up using three eQTL databases was used to identify putative causal genes. Finally, we used a polygenic risk score approach to determine the contribution to IPF disease risk of genetic variants that have not been reported as associated with IPF risk. For that, variants that were located near known IPF risk signals were excluded from the score and the number of variants included was varied. Results GWAS were performed on 10,790,934 genetic variants in 2,668 IPF cases and 8,591 controls (stage 1) with replication in 1,467 IPF cases and 11,874 controls (stage 2). We identified three novel signals associated with IPF susceptibility. These three novel signals were associated with decreased expression of DEPTOR (in lung tissue), KIF15 and MAD1L1 (in non-lung tissue). We replicated 11 of the previously reported 17 IPF risk variants. The most significant risk score was found to include over 800,000 independent variants that were non-significant in our GWAS and explained about 2% of the phenotypic variation. Conclusion The novel signals support the importance of mTOR signalling and suggest a possible role of spindle-assembly genes in IPF susceptibility. Risk score analyses suggest there are potentially hundreds of genetic variants associated with IPF susceptibility that have not yet been identified by GWAS.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,009 | 0,015 |
| Méta-épidémiologie (sens strict) | 0,003 | 0,001 |
| Méta-épidémiologie (sens large) | 0,004 | 0,031 |
| Bibliométrie | 0,004 | 0,005 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,003 | 0,001 |
| Science ouverte | 0,002 | 0,001 |
| Intégrité de la recherche | 0,002 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».