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Heterozygous rare genetic variants in non-syndromic early-onset obesity.

ABSTRACT: BACKGROUND:Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. OBJECTIVE:We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). METHODS:Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. RESULTS:Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. CONCLUSIONS:Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.

SUBMITTER: Serra-Juhe C

PROVIDER: S-EPMC7101277 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Heterozygous rare genetic variants in non-syndromic early-onset obesity.

Serra-Juhé Clara C Martos-Moreno Gabriel Á GÁ Bou de Pieri Francesc F Flores Raquel R Chowen Julie A JA Pérez-Jurado Luis A LA Argente Jesús J

International journal of obesity (2005) 20190329 4

<h4>Background</h4>Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions.<h4>Objective</h4>We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes ...[more]

PMID: 30926952

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Project 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.

Project description:ImportanceAlthough rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.ObjectivesTo assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations.Design, setting, and participantsIn this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged ≤66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes. Recruitment took place from July 1, 2015, to June 30, 2019. Data were analyzed from February 1 to February 28, 2020.ExposuresRare and novel variants categorized as pathogenic or likely pathogenic.Main outcomes and measuresThe prevalence of rare and novel pathogenic variants in African American and Hispanic/Latinx probands with early-onset AF and genotype-phenotype associations.ResultsAmong 227 probands with early-onset AF, mean (SD) age at onset of AF was 51.0 (9.9) years, 132 probands (58.1%) were men, 148 (65.2%) were African American, and 79 (34.8%) were Hispanic/Latinx. A family history of AF was verified in 24 probands with early-onset AF (10.6%). Sequencing 60 candidate genes identified 53 (23 rare and 30 novel) variants with 16 of the 227 (7.0%) probands harboring likely pathogenic (43.8%) or pathogenic (56.2%) variants, with most loss-of-function variants in TTN, the gene encoding the sarcomeric protein titin (46.7%). In 6 families with more than 2 affected members, variants of unknown significance in sodium channel (SCN10A), potassium channel (KCNE5), sarcomeric proteins (MYH6 and TTN), and atrial natriuretic peptide (NPPA) cosegregated with AF.Conclusions and relevanceIn this study, likely pathogenic and pathogenic variants were identified, with most loss-of-function variants in TTN, that increase susceptibility to early-onset AF in African American and Hispanic/Latinx individuals. These findings provide further understanding toward molecular phenotyping of AF and suggest novel mechanism-based therapeutic approaches for this common arrhythmia in ethnic minority groups.

Dataset Information

Heterozygous rare genetic variants in non-syndromic early-onset obesity.

Publications

Heterozygous rare genetic variants in non-syndromic early-onset obesity.

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