Repeat length variations in polyglutamine disease-associated genes affect body mass index

Area of Science:

• Genetics
• Obesity Research
• Molecular Biology

Background:

• Obesity prevalence is rapidly increasing globally, posing significant health risks.
• While heritability contributes to body mass index (BMI) variation, genome-wide association studies (GWAS) have only explained a small fraction of this heritability.
• This study addresses the 'missing heritability' of obesity by investigating DNA repeat length polymorphisms, which are undetectable by GWAS.

Purpose of the Study:

• To investigate the association between cytosine-adenine-guanine (CAG) repeat length polymorphisms and body mass index (BMI).
• To identify novel genetic risk factors contributing to obesity.
• To explore the role of the brain in obesity pathophysiology.

Main Methods:

• CAG repeat length was determined in nine known polyglutamine disease-associated genes.
• Data was collected from two large cohorts comprising 12,457 individuals.
• Associations with BMI were analyzed using generalized linear mixed-effect models.

Main Results:

• A significant association was found between BMI and CAG repeat length in seven polyglutamine disease-associated genes.
• These repeat variations accounted for 0.75% of the total BMI variation.
• Genes with significant associations include ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, and AR.

Conclusions:

• Repeat polymorphisms constitute an important, novel class of genetic risk factors for obesity.
• The findings highlight the involvement of the brain in the pathophysiology of obesity.
• Further research into repeat polymorphisms may uncover additional genetic contributions to obesity.