Polymorphisms of the CREB-regulated transcription coactivator 1 gene contribute to the genetics of human obesity in psychiatric patients and in the general population, results from a novel study demonstrated.
Specifically, the CRTC1 nonsynonymous polymorphism rs3746266A>G was associated with body mass index in three independent psychiatric samples in which lower BMI values were measured in carriers of the G allele compared with noncarriers, while the protective effect of the T allele of rs6510997C>T (a proxy of rs3746266A>G) against fat accumulation also was observed in a large population-based sample.
"Psychiatric, psychological, sociodemographic, and behavioral factors, as well as heritability, have been shown to influence individual susceptibility to overweight or obesity, both in the general population and in psychiatric patients before and after treatment with potentially weight gain–inducing psychotropic drugs," researchers led by Eva Choong, Pharm.D., Ph.D., reported online Aug. 7 in JAMA Psychiatry. "Genome-wide association studies conducted to date only explain a small fraction of body mass index (BMI) heritability, and more obesity susceptibility genes remain to be discovered."
For the study, which is thought to be the first of its kind, researchers from two university hospitals and a private clinic in Switzerland evaluated the effect of three CRTC1 polymorphisms on BMI and/or fat mass in a cohort of 152 patients taking weight gain–inducing psychotropic drugs (sample 1). The CRTC1 variant that was significantly associated with BMI was then replicated in two independent psychiatric samples, which consisted of 174 patients in sample 2 and 118 patients in sample 3, and in two white population-based samples, which consisted of 5,338 patients in sample 4 and 123,865 patients in sample 5 (JAMA Psychiatry 2013 Aug. 7 [doi: 10.1001/jamapsychiatry.2013.187]).
The researchers found that in the three psychiatric samples, carriers of the CRTC1 rs3746266A>G allele had a lower BMI than did noncarriers (P = .001 in sample 1, P = .05 in sample 2, and P = .0003 in sample 3). In a combined analysis that excluded patients taking other weight gain–inducing drugs, G-allele carriers had a 1.81-kg/m2 lower BMI, compared with noncarriers (P less than .0001). The strongest association was seen in women age 45; in this subset of patients, G-allele carriers had a 3.87-kg/m2 lower BMI, compared with noncarriers (P less than .0001).
In the analysis of population-based samples, the T allele of rs651099C>T, which is a proxy of the G allele, was associated with lower BMI (P = .01 in sample 5) and fat mass (P = .03 in sample 4).
The investigators acknowledged several limitations of their study. For example, most patients were not drug naive and had already developed weight gain because of previous treatments. "It was therefore not possible to determine with certainty whether the strong association of CRTC1 genotypes with BMI and fat mass in psychiatric populations was due to the psychiatric illness and/or to the pharmacological treatment," they wrote. "Extensive hormonal measurements were not available for our samples, so the role of sex hormones on the association of CRTC1 variants with adiposity could not be explored."
In addition, the racial and ethnic makeup of the patients sampled means that the results are not generalizable.
Despite those limitations, Dr. Choong expressed optimism about where these results might lead. "Our results suggest that CRTC1 plays an important role in the high prevalence of overweight and obesity observed in psychiatric patients," she and her colleagues concluded. "Besides, CRTC1 could play a role in the genetics of obesity in the general population, thereby increasing our understanding of the multiple mechanisms influencing obesity.
"Finally, the strong associations of CRTC1 variants with adiposity in women younger than 45 years support further research on the interrelationship between adiposity and the reproductive function."
The study was funded in part by the Swiss National Research Foundation and by the National Center of Competence in Research, which is funded by the Swiss National Science Foundation. Dr. Choong had no disclosures; several of her colleagues disclosed that they have received grants or honoraria from numerous pharmaceutical companies.