Author:
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Serra Juhe, Clara; Martos Moreno, Gabriel A.; Bou de Pieri, Francesc; Flores, Raquel; González, Juan Ramón; Rodríguez Santiago, Benjamín; Argente, Jesús; Pérez Jurado, Luis
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Abstract:
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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. |