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: Serra Juhe, Clara, Martos Moreno, Gabriel A., Bou de Pieri, Francesc, Flores, Raquel, González, Juan Ramón, Rodríguez Santiago, Benjamín, Argente, Jesús, Pérez Jurado, Luis A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/112230
Acceso en línea:https://hdl.handle.net/2445/112230
Access Level:acceso abierto
Palabra clave:Obesitat
Genètica humana
Obesity
Human genetics
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spelling Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variantsSerra Juhe, ClaraMartos Moreno, Gabriel A.Bou de Pieri, FrancescFlores, RaquelGonzález, Juan RamónRodríguez Santiago, BenjamínArgente, JesúsPérez Jurado, Luis A.ObesitatGenètica humanaObesityHuman geneticsObesity 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.PLOS2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/112230Articles publicats en revistes (ISGlobal)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1006657PLoS Genetics, 2017, vol. 13, num. 5, p. e1006657http://dx.doi.org/10.1371/journal.pgen.1006657cc by (c) Serra et al., 2017http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1122302026-05-27T06:46:51Z
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 Juhe, Clara
Obesitat
Genètica humana
Obesity
Human genetics
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 Juhe, Clara
Martos Moreno, Gabriel A.
Bou de Pieri, Francesc
Flores, Raquel
González, Juan Ramón
Rodríguez Santiago, Benjamín
Argente, Jesús
Pérez Jurado, Luis A.
author Serra Juhe, Clara
author_facet Serra Juhe, Clara
Martos Moreno, Gabriel A.
Bou de Pieri, Francesc
Flores, Raquel
González, Juan Ramón
Rodríguez Santiago, Benjamín
Argente, Jesús
Pérez Jurado, Luis A.
author_role author
author2 Martos Moreno, Gabriel A.
Bou de Pieri, Francesc
Flores, Raquel
González, Juan Ramón
Rodríguez Santiago, Benjamín
Argente, Jesús
Pérez Jurado, Luis A.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Obesitat
Genètica humana
Obesity
Human genetics
topic Obesitat
Genètica humana
Obesity
Human genetics
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
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 https://hdl.handle.net/2445/112230
url https://hdl.handle.net/2445/112230
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1006657
PLoS Genetics, 2017, vol. 13, num. 5, p. e1006657
http://dx.doi.org/10.1371/journal.pgen.1006657
dc.rights.none.fl_str_mv cc by (c) Serra et al., 2017
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Serra et al., 2017
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv PLOS
publisher.none.fl_str_mv PLOS
dc.source.none.fl_str_mv Articles publicats en revistes (ISGlobal)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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