Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs.

Détails

Ressource 1Télécharger: 39332408.pdf (6302.35 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_CF9C4365E9CD
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs.
Périodique
American journal of human genetics
Auteur⸱e⸱s
Auwerx C., Moix S., Kutalik Z., Reymond A.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
07/11/2024
Peer-reviewed
Oui
Volume
111
Numéro
11
Pages
2347-2361
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between the region's copy number and 117 complex traits and diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by 16p11.2 BP4-5 CNVs, with the deletion-only, mirror, U-shape, and duplication-only models being the best fit for 30, 10, 4, and 2 phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, or educational attainment (EA), we found that sixteen testable deletion-driven associations-primarily with cardiovascular and metabolic traits-were BMI dependent, with EA playing a more subtle role and no association depending on height. Bidirectional Mendelian randomization supported that 13 out of these 16 associations were secondary consequences of the CNV's impact on BMI. For the 23 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that 10 phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, and pneumonia and acute kidney injury risk, remained associated under strict Bonferroni correction, with 10 additional nominally significant associations. These results paint a complex picture of 16p11.2 BP4-5's pleiotropic pattern that involves direct effects on multiple physiological systems and indirect co-morbidities consequential to the CNV's impact on BMI and EA, acting through trait-specific dosage mechanisms.
Mots-clé
Humans, Chromosomes, Human, Pair 16/genetics, DNA Copy Number Variations, Genetic Pleiotropy, Body Mass Index, Genome-Wide Association Study, Phenotype, Female, Male, Mendelian Randomization Analysis, Chromosome Deletion, United Kingdom, Middle Aged, Chromosome Disorders/genetics, Adult, Mendelian randomization, dosage sensitivity, educational attainment, genomic disorder, mediation, multi-system disorder, obesity, phenome-wide association study, pleiotropy, structural variant
Pubmed
Open Access
Oui
Création de la notice
04/10/2024 14:23
Dernière modification de la notice
15/11/2024 20:37
Données d'usage