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

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...

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Autores principales: Serra-Juhé, Clara, Martos-Moreno, Gabriel Á., Bou de Pieri, Francesc, Flores, Raquel, González, Juan R., Rodríguez-Santiago, Benjamín, Argente, Jesús, Pérez-Jurado, Luis A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443539/
https://www.ncbi.nlm.nih.gov/pubmed/28489853
http://dx.doi.org/10.1371/journal.pgen.1006657
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author Serra-Juhé, Clara
Martos-Moreno, Gabriel Á.
Bou de Pieri, Francesc
Flores, Raquel
González, Juan R.
Rodríguez-Santiago, Benjamín
Argente, Jesús
Pérez-Jurado, Luis A.
author_facet Serra-Juhé, Clara
Martos-Moreno, Gabriel Á.
Bou de Pieri, Francesc
Flores, Raquel
González, Juan R.
Rodríguez-Santiago, Benjamín
Argente, Jesús
Pérez-Jurado, Luis A.
author_sort Serra-Juhé, Clara
collection PubMed
description 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.
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spelling pubmed-54435392017-06-06 Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants Serra-Juhé, Clara Martos-Moreno, Gabriel Á. Bou de Pieri, Francesc Flores, Raquel González, Juan R. Rodríguez-Santiago, Benjamín Argente, Jesús Pérez-Jurado, Luis A. PLoS Genet Research Article 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. Public Library of Science 2017-05-10 /pmc/articles/PMC5443539/ /pubmed/28489853 http://dx.doi.org/10.1371/journal.pgen.1006657 Text en © 2017 Serra-Juhé et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Serra-Juhé, Clara
Martos-Moreno, Gabriel Á.
Bou de Pieri, Francesc
Flores, Raquel
González, Juan R.
Rodríguez-Santiago, Benjamín
Argente, Jesús
Pérez-Jurado, Luis A.
Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
title Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
title_full Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
title_fullStr Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
title_full_unstemmed Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
title_short Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
title_sort novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443539/
https://www.ncbi.nlm.nih.gov/pubmed/28489853
http://dx.doi.org/10.1371/journal.pgen.1006657
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