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...

Descripción completa

Detalles Bibliográficos
Autores: Serra Juhé, Clara, 1984-, Martos Moreno, Gabriel A., Bou de Pieri, Francesc, 1992-, Flores Peirats, Raquel, González Ruiz, Juan Ramón, Rodríguez Santiago, Benjamín, Argente, Jesús, Pérez Jurado, Luis Alberto
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/32500
Acceso en línea:http://hdl.handle.net/10230/32500
http://dx.doi.org/10.1371/journal.pgen.1006657
Access Level:acceso abierto
Palabra clave:Obesity
Body mass index
Childhood obesity
Glutamate
ADHD
Spanish people
Alleles
Copy number variation
id ES_4d2f4ff720b645ce1d52d3240db81aaa
oai_identifier_str oai:repositori.upf.edu:10230/32500
network_acronym_str ES
network_name_str España
repository_id_str
spelling Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variantsSerra Juhé, Clara, 1984-Martos Moreno, Gabriel A.Bou de Pieri, Francesc, 1992-Flores Peirats, RaquelGonzález Ruiz, Juan RamónRodríguez Santiago, BenjamínArgente, JesúsPérez Jurado, Luis AlbertoObesityBody mass indexChildhood obesityGlutamateADHDSpanish peopleAllelesCopy number variationObesity 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.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.Public Library of Science (PLoS)201720172017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/32500http://dx.doi.org/10.1371/journal.pgen.1006657reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésPlos Genetics. 2017;13(5):e1006657© 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.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/325002026-06-12T07:21:37Z
dc.title.none.fl_str_mv 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
spellingShingle Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
Serra Juhé, Clara, 1984-
Obesity
Body mass index
Childhood obesity
Glutamate
ADHD
Spanish people
Alleles
Copy number variation
title_short 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_sort Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
dc.creator.none.fl_str_mv Serra Juhé, Clara, 1984-
Martos Moreno, Gabriel A.
Bou de Pieri, Francesc, 1992-
Flores Peirats, Raquel
González Ruiz, Juan Ramón
Rodríguez Santiago, Benjamín
Argente, Jesús
Pérez Jurado, Luis Alberto
author Serra Juhé, Clara, 1984-
author_facet Serra Juhé, Clara, 1984-
Martos Moreno, Gabriel A.
Bou de Pieri, Francesc, 1992-
Flores Peirats, Raquel
González Ruiz, Juan Ramón
Rodríguez Santiago, Benjamín
Argente, Jesús
Pérez Jurado, Luis Alberto
author_role author
author2 Martos Moreno, Gabriel A.
Bou de Pieri, Francesc, 1992-
Flores Peirats, Raquel
González Ruiz, Juan Ramón
Rodríguez Santiago, Benjamín
Argente, Jesús
Pérez Jurado, Luis Alberto
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Obesity
Body mass index
Childhood obesity
Glutamate
ADHD
Spanish people
Alleles
Copy number variation
topic Obesity
Body mass index
Childhood obesity
Glutamate
ADHD
Spanish people
Alleles
Copy number variation
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.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/32500
http://dx.doi.org/10.1371/journal.pgen.1006657
url http://hdl.handle.net/10230/32500
http://dx.doi.org/10.1371/journal.pgen.1006657
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Plos Genetics. 2017;13(5):e1006657
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869407675356282880
score 15,81155

Similares en LA Referencia