Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/112230
Title: Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
Author: Serra Juhe, Clara
Martos Moreno, Gabriel A.
Bou de Pieri, Francesc
Flores, Raquel
González, Juan R.
Rodríguez Santiago, Benjamin
Argente, Jesús
Pérez Jurado, Luis
Keywords: Obesitat
Genètica humana
Obesity
Human genètics
Issue Date: 10-May-2017
Publisher: PLOS
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.
Note: Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pgen.1006657
It is part of: PLoS Genetics, 2017, vol. 13, num. 5, p. e1006657
Related resource: http://dx.doi.org/10.1371/journal.pgen.1006657
URI: http://hdl.handle.net/2445/112230
ISSN: 1553-7390
Appears in Collections:Articles publicats en revistes (ISGlobal)

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