*Genetics of childhood obesity* (basic protocol for the Netherlands Epidemiology of Obesity in children study)

The current prevalence of childhood overweight and obesity is alarmingly high.
Childhood obesity is associated with considerable health risks and it resists
most available treatments. There is a substantial genetic contribution to
obesity. In addition, epigenetic mechanisms play a role. The known genetic risk
factors for obesity explain only a limited part of the variance in body mass
index (BMI). A better characterization of the genetic risk factors for
childhood obesity will ultimately lead to improved treatment and prevention
strategies. We propose that (epi-)genetic variation in genes involved in the
regulation of addicitive behaviour and satiety plays a major role in the
development of obesity. We aim to study (epi-)genetic variation in these genes
using family-based association and linkage analysis in a large cohort of obese
children and adolescents. In addition to the studies of common obesity, we
would like to study monogenic forms of obesity. The most common monogenic form
of obesity is caused by mutations in the gene encoding the melanocortin 4
receptor (MC4R). This receptor plays a central role in homeostatic aspects of
energy balance. We plan to perform mutation analysis of MC4R in the cohort. Our
cohort is uniquely suited to study the role of MC4R mutations in obesity.

We propose that variation in genes involved in the regulation of motivational
behaviour and satiety plays a major role in the development of obesity. We aim
to identify these genes using family-based association and linkage analysis in
a large cohort of obese children and adolescents.

In addition, we plan to perform mutation analysis of the gene encoding the
melanocortin 4 receptor (MC4R) in our cohort with the aim to study the role of
MC4R mutations in obesity.

We will establish a centre for childhood obesity at Leiden Univeristy Medical
Center (LUMC). In this centre, we will collect a variety of data for diagnostic
and treatment purposes. These data include anthropometric measures, oral
glucose tolerance response, endocrine measures, information about dietary
intake, physical activity, socio-economic status, and ethnicity. We aim to
collect DNA of the patients of our centre and their parents and siblings. All
patient samples will be screened for mutations in the melanocortin-4 receptor
gene (MC4R). We will study the phenotypic characteristics of patients with and
without MC4R mutations. If we do not find defects in MC4R in the DNA of a
patient, the sample will be stored in our DNA bank for future candidate gene
studies and family based association or linkage studies.

We propose to ask patients and their parents for consent to withdraw blood
samples for our genetic studies. Sampling of the children and adolescents will
be performed simultaneously with blood withdrawal for diagnostic purposes.
Consequently, there is no extra burden for patients. Parents and siblings of
the patients will undergo venipuncture once. In some cases we will collect DNA
using buccal swabs or a DNA Self-Collection Kit (to collect DNA from saliva).
This will be the preferred method for very young children and. In the future,
this study should lead to improved treatment methods.