# name
Novel genes involved in severe early-onset obesity revealed by
                rare copy number and sequence variants

# metadata.dc.description.abstract[].value
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.

# metadata.dc.relation.isformatof[].value
Reproducció del document publicat a:
                http://dx.doi.org/10.1371/journal.pgen.1006657

# metadata.dc.source[].value
Articles publicats en revistes (ISGlobal)

# metadata.dc.title[].value
Novel genes involved in severe early-onset obesity revealed by
                rare copy number and sequence variants