Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants
Serra-Juhe, Clara (Hospital del Mar (Barcelona, Catalunya))
Martos-Moreno, Gabriel Á. (Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición)
Bou de Pieri, Francesc (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Flores, Raquel (Centro de Investigación Biomédica en Red de Enfermedades Raras)
González, Juan Ramón (Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública)
Rodríguez-Santiago, Benjamín (Quantitative Genomic Medicine Laboratories (Esplugues de Llobregat, Barcelona))
Argente, Jesús (IMDEA Food Institute (Madrid))
Pérez-Jurado, Luis Alberto (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Universitat Autònoma de Barcelona

Data:	2017
Resum:	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. Although there is strong evidence for a high genetic component of obesity, the underlying genetic causes are largely unknown, mostly due to the highly heterogeneous nature of the disorder. In this work, we have focused on the most severe end of the spectrum, severe obesity with early-onset in childhood, which is more likely due to genetic alterations. We screened for rare copy number variation (CNV) a sample of 157 Spanish children with early-onset obesity using molecular karyotypes and then studied the genes altered by CNVs in 480 cases and 480 non-obese controls. We identified a higher burden of gain-type CNVs in cases as well as several CNVs and sequence variants that were specific of the obese population. Interestingly, the genes identified shared co-expression partners with known obesity genes. Among those, the genes encoding the neuropeptide Y (NPY), two glutamate receptors (GRIK1, GRM7), the X-linked gastrin-peptide receptor (GRPR), and the organic anion transporter (SLCO4C1) are novel obesity candidate genes that may contribute to highly penetrant forms of familial obesity.
Ajuts:	Generalitat de Catalunya 2014SRG1468 Ministerio de Economía y Competitividad MDM-2014-0370 Ministerio de Economía y Competitividad PI1302481 Ministerio de Economía y Competitividad PI13/02195 Ministerio de Ciencia e Innovación MTM2011-26515 Ministerio de Ciencia e Innovación MTM2010-09526-E
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PLOS genetics, Vol. 13 (may 2017) , ISSN 1553-7404

DOI: 10.1371/journal.pgen.1006657
PMID: 28489853

19 p, 1.1 MB

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