Identification of rare sequencing variants with a larger functional impact has the potential to highlight new pathways contributing to obesity. Using whole exome-sequencing followed by genotyping, we have identified a low-frequency coding variant rs2076349 (V527M) in the laminin subunit beta 3 (LAMB3) gene showing strong association with morbid obesity and thereby risk of type 2 diabetes. We exome-sequenced 200 morbidly obese subjects and 100 controls with pooled DNA samples. After several filtering steps, we retained 439 obesity-enriched low-frequency-coding variants. Associations between genetic variants and obesity were validated sequentially in two case-control cohorts. In the final analysis of 1,911 morbidly obese and 1,274 controls, rs2076349 showed strong association with obesity (p = 9.67 x 10-5, OR = 1.84). This variant was also associated with body mass index (BMI) and fasting serum leptin. Moreover, LAMB3 expression in adipose tissue was positively correlated with BMI and adipose morphology (few but large fat cells). LAMB3 knockdown by siRNA in human adipocytes cultured in vitro inhibited adipogenesis. In conclusion, we identified a previously not reported low-frequency coding variant that was associated with morbid obesity in the LAMB3 gene. This gene may be involved in the development of excess body fat.
- Received April 24, 2016.
- Accepted July 11, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.