Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants

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  • dc.contributor.author Serra Juhé, Clara, 1984-ca
  • dc.contributor.author Martos Moreno, Gabriel A.ca
  • dc.contributor.author Bou de Pieri, Francesc, 1992-ca
  • dc.contributor.author Flores Peirats, Raquelca
  • dc.contributor.author González Ruiz, Juan Ramónca
  • dc.contributor.author Rodríguez Santiago, Benjamínca
  • dc.contributor.author Argente, Jesúsca
  • dc.contributor.author Pérez Jurado, Luis Albertoca
  • dc.date.accessioned 2017-07-04T07:59:41Z
  • dc.date.available 2017-07-04T07:59:41Z
  • dc.date.issued 2017
  • dc.description.abstract Obesity is a multifactorial disorder with high heritability (50–75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.
  • dc.description.sponsorship LAPJ 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 program), and the Spanish Ministry of Economy and Competiveness “Programa de Excelencia María de Maeztu” (MDM-2014-0370). JA was funded by the Spanish Ministry of Health (FIS-PI13/02195 & PI16/00485, co-funded by FEDER) and the Fundación de Endocrinología y Nutrición. JRG was supported by the Spanish Ministry of Science and Innovation (MTM2011-26515) and Statistical Genetics Network - GENOMET (MTM2010-09526-E). The "Centro de Investigación Biomèdica en Red" for rare diseases (CIBERER), obesity and nutrition (CIBEROBN), and epidemiology and public health (CIBERESP) are initiatives of the Instituto de Salud Carlos III, Spain.
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Serra Juhé C, Martos Moreno GA, Bou de Pieri F, Flores Peirats R, González JR, Rodríguez Santiago B et al. Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants. Plos Genetics. 2017;13(5):e1006657. DOI: 10.1371/journal.pgen.1006657
  • dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1006657
  • dc.identifier.issn 1553-7390
  • dc.identifier.uri http://hdl.handle.net/10230/32500
  • dc.language.iso eng
  • dc.publisher Public Library of Science (PLoS)ca
  • dc.relation.ispartof Plos Genetics. 2017;13(5):e1006657
  • dc.rights © 2017 Serra-Juhé et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Obesity
  • dc.subject.keyword Body mass index
  • dc.subject.keyword Childhood obesity
  • dc.subject.keyword Glutamate
  • dc.subject.keyword ADHD
  • dc.subject.keyword Spanish people
  • dc.subject.keyword Alleles
  • dc.subject.keyword Copy number variation
  • dc.title Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variantsca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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