Obesity is a growing global health concern, with projections estimating that approximately 50% of adults in the United States will be obese by 2030. The prevalence of obesity in adults has increased significantly, from 30.5% to 41.9% between 1999 and 2023, while severe obesity has risen from 4.7% to 9.2%. While lifestyle and environmental factors play a crucial role, genetics are estimated to contribute 30-50% to the risk of obesity. Recent research has begun to uncover specific genes that may play a role in weight regulation. This article delves into a groundbreaking study that identifies a link between rare variants in the BSN gene and an increased risk of obesity.
The Role of Genetics in Obesity
Twin and genome-wide association studies (GWAS) suggest that the risk of obesity is 30-50% heritable. This means that a person's genes can significantly influence their likelihood of gaining weight. While changes in genetics cannot account for the rapid increase in obesity rates, they do affect an individual's susceptibility to weight gain in environments where food is readily available. Genome-wide association studies have identified many common genetic variants associated with body weight regulation. Polygenic risk scores, which aggregate large numbers of genetic variants, can predict obesity deciles in some genetic ancestries. However, currently known genome-wide significant loci only explain about 6% of the variation in body mass index (BMI).
Identifying New Obesity Risk Genes
To identify new genetic contributors to obesity, researchers have turned to exome sequencing of large numbers of individuals. This approach has proven successful in discovering rare genetic contributors to other quantitative traits, such as height, celiac disease, and dyslipidemia. Recent advances in obesity and hyperlipidemia treatments have leveraged human genetics to identify genes contributing to extreme phenotypes, understand biological mechanisms, and develop novel interventions. The availability of large-scale exome/genome sequencing data from the United Kingdom Biobank (UKBB) and All of Us research program has further extended the ability to assess rare variants at a large scale.
The BSN Gene: A Potential Key to Understanding Obesity
A recent study combined data from the UKBB, an extreme obesity cohort at Columbia University, and the All of Us research program to identify new obesity risk genes. The study focused on rare, likely damaging variants in the genome. The researchers performed an exome-wide association analysis of ultra-rare variants in approximately 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. The researchers discovered that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI. The association of BSN with BMI was replicated in the All of Us whole genome sequencing data.
Study Methodology
The study utilized data from three cohorts:
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- UK Biobank (UKBB): Exome sequence data and basic phenotype information were analyzed for 144,496 individuals of European ancestry. Individuals with a history of cancer or eating disorders were excluded. The UKBB data served as the discovery cohort for association of rare variants and BMI.
- Columbia University Early Onset and/or Extreme Obesity Cohort: This cohort consisted of 1598 individuals from 903 families, with approximately half being pediatric and half adults. Samples were exome sequenced.
- All of Us Research Program: Whole genome sequencing and clinical data were available for 98,622 individuals. Data from 47,897 unrelated individuals of European ancestry were used for replication.
The researchers performed an exome-wide scan of risk genes through a linear regression of BMI over counts of rare damaging variants using the UKBB data. They tested seven different ways of combining rare variants, including protein truncating variants and predicted damaging missense variants. The association test was carried out using REGENIE, with age, Townsend deprivation index at recruitment, smoking/alcohol status, sex, principal components, and genetic heterozygosity as covariates.
Key Findings
The study identified two genes associated with BMI with exome-wide significance, one of which is MC4R. The association of BSN with BMI is primarily driven by protein-truncating variants and damaging missense variants with REVEL > 0.75. Twenty-seven individuals have heterozygous genotypes for one of these variants. The BMI density distribution for pLoF BSN heterozygotes is shifted to a higher BMI than the overall UKBB cohort.
The researchers also identified two heterozygous pLoF BSN alleles in the Columbia cohort:
- RU2487: A 23-year-old Latina woman with a history of severe obesity and type 2 diabetes mellitus, who is heterozygous for a de novo p.Gln703X allele in BSN. She had gastric bypass surgery for weight loss but experienced weight regain.
- RU2617: An African American female heterozygous for a p.R3494X variant in BSN. She had a history of obstructive sleep apnea and impaired fasting blood glucose.
Replication in the All of Us cohort showed that 12 European individuals were heterozygous for BSN pLoF variants, with an average BMI of 37.0 kg/m2. Linear regression analysis found a significant association between BMI and BSN genotype.
What is the BSN Gene?
BSN, which stands for bassoon, is a gene that provides instructions for making a protein called bassoon. The bassoon protein is primarily expressed in the brain, inner hair cells of the ear, and the retina of the eye. In the brain, bassoon is found in the synapses of glutamatergic neurons and neurons in the hypothalamus, which are involved in controlling appetite and eating behaviors.
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Bassoon's Role in Neurotransmission
Bassoon is a presynaptic scaffold protein located in the cytomatrix at the active zone (CAZ) of synapses. It plays a crucial role in orchestrating the release of neurotransmitters, which are chemical messengers that transmit signals between nerve cells. Bassoon participates in the formation of Piccolo-Bassoon transport vesicles that are transported to newly formed synapses. It is one of several scaffolding proteins within the presynaptic cytomatrix, working alongside Piccolo (PCLO), RIM, MUNC13, and ELKS.
Implications of BSN Variants on Obesity
The expression of BSN throughout the brain suggests that gene dosage could contribute to hyperphagia (excessive eating) through both homeostatic and hedonic circuits. Homeostatic circuits regulate energy balance and hunger, while hedonic circuits are involved in the reward and pleasure associated with eating. The study implicates heterozygous pLoF variants in BSN as a new genetic etiology for human obesity that is not associated with adverse impact on cognition or other neurobehavioral phenotypes.
Red Mountain Weight Loss and Individualized Programs
It's important to note that genetics is just one piece of the puzzle when it comes to weight loss. Individualized weight loss programs that consider a person's health history, lifestyle, and weight loss goals are crucial for success. For example, Red Mountain Weight Loss offers personalized programs that include a one-on-one consultation with a licensed medical provider. They also require lab work to ensure patient safety. These programs often involve medication to help regulate blood sugar levels, insulin, and digestion, promoting a feeling of fullness and satisfaction.
Lifestyle and Dietary Considerations
While medication can be a helpful tool, maintaining a healthy diet is essential for maximizing weight loss results. A balanced diet that focuses on counting servings rather than calories, with a combination of lean proteins, vegetables, and healthy fats, is often recommended. Additionally, regular physical activity and stress management techniques can contribute to overall well-being and weight management.
Ram 1500 Rebel Packages: A Tangential Note
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