Heterozygous rare genetic variants in non-syndromic early-onset obesity

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  • dc.contributor.author Serra Juhé, Clara, 1984-
  • dc.contributor.author Martos Moreno, Gabriel A.
  • dc.contributor.author Bou de Pieri, Francesc, 1992-
  • dc.contributor.author Flores, Raquel
  • dc.contributor.author Chowen, Julie A.
  • dc.contributor.author Pérez Jurado, Luis Alberto
  • dc.contributor.author Argente, Jesús
  • dc.date.accessioned 2019-07-05T07:16:05Z
  • dc.date.available 2019-07-05T07:16:05Z
  • dc.date.issued 2020
  • dc.description.abstract BACKGROUND: Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. OBJECTIVE: We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). METHODS: Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. RESULTS: Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. CONCLUSIONS: Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.
  • dc.description.sponsorship JA was funded by the Spanish Ministry of Health (FIS-PI13/02195 and PI16/00485, co-funded by FEDER), the Fundación de Endocrinología y Nutrición and the “Centro de Investigación Biomédica en Red” for obesity and nutrition (CIBEROBN) of the Instituto de Salud Carlos III, Spain. LAP-J was funded by the Spanish Ministry of Health (FIS-PI1302481, co-funded by FEDER), the Generalitat de Catalunya (2014SRG1468), the Institució Catalana de Recerca i Estudis Avançats (ICREA Academia programme), the Spanish Ministry of Economy and Competiveness “Programa de Excelencia María de Maeztu” (MDM-2014-0370) and the Centro de Investigación Biomédica en Red for rare diseases (CIBERER) of the Instituto de Salud Carlos III, Spain. JAC was funded by grants from the Spanish Ministry of Science and Innovation (BFU2017-82565-C21-R2). We would like to thank Francisca Díaz and Sandra Canelles for their excellent technical assistance.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Serra-Juhé C, Martos-Moreno GÁ, Bou de Pieri F, Flores R, Chowen JA, Pérez-Jurado LA et al. Heterozygous rare genetic variants in non-syndromic early-onset obesity. Int J Obes (Lond). 2020;44:830-41. DOI 10.1038/s41366-019-0357-5
  • dc.identifier.doi http://dx.doi.org/10.1038/s41366-019-0357-5
  • dc.identifier.issn 0307-0565
  • dc.identifier.uri http://hdl.handle.net/10230/41951
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Int J Obes (Lond). 2020;44:830-41
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-82565-C21-R2
  • dc.rights © 2019 Clara Serra-Juhé et al. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Endocrine system and metabolic diseases
  • dc.subject.keyword Endocrinology
  • dc.title Heterozygous rare genetic variants in non-syndromic early-onset obesity
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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