CRTC1 may play role in weight regulation

Researchers found a link between genetic polymorphisms of CRTC1  and differences in BMIs in psychiatric patients, with a weaker association observed in the general population, according to data reported in JAMA Psychiatry.

“The genetic influence on obesity appears much stronger in psychiatric populations than in the general population, possibly because of the high prevalence of illness- and/or pharmacological treatment-related obesity in the former populations,” Chin B. Eap, PhD, one of the study authors and professor of pharmacogenetics and psychopharmacology at the Faculty of biology and medicine of the University of Lausanne, told Endocrine Today.

Previous research in mice has suggested the CREB-regulated transcription coactivator 1 (CRTC1) is associated with hypothalamic control of food intake, and low energy expenditure were observed in mice without the gene.

Eap and colleagues retrospectively assessed data from a Swiss cohort of 152 psychiatry patients (sample 1) taking weight gain-inducing psychotropic drugs. The TaqMan allelic discrimination assay (Applied Biosystems) was used for patient genotyping.

Data indicate that rs3746266A>G, a CRTC1 polymorphism, was significantly associated with BMI in this cohort (P=.003). The difference in BMI between patients with the G allele and in non-carriers was 2.13 kg/m² (95% CI, 0.62-3.49; P=.001).

Researchers replicated this variant in two independent psychiatric samples (sample 2, n=174; sample 3, n=118) and two white population-based samples, they wrote.

Samples 2 and 3 also demonstrated the association between carriers of the G allele and lower BMI ratings (sample 2, P=.05; sample 3, P=.0003).

In a combination analysis, which excluded patients taking additional weight-gain inducing medications, a generalized additive mixed model indicated that the 98 patients with the G allele had a 1.81 kg/m² lower BMI than those without (n=226; P<.0001). In the sex-stratified analysis, G allele carrying-women aged younger than 45 years had a significant BMI decrease of 3.87 kg/m² (P<.0001).

Besides genetic polymorphism, researchers also found age (0.09 kg/m² increase per year; P<.0001) and the type of psychotropic medication (1.41 kg/m² higher with antipsychotics vs. mood stabilizers; P=.003) impacted BMI.

In the population-based samples, Cohorte Lausannoise (n=5,338; CoLaus) and the Genetic Investigation of Anthropometric Traits (n=123,865; GIANT), researchers analyzed data for the CRTC1 polymorphism rs6510997C>T.

In CoLaus, researchers found no link between the T allele (T allele of rs6510997 being a proxy of the rs3746266 G allele) and BMI, weight and waist circumference. However, there was a significant association with fat mass (P=.03), with the strongest association apparent in premenopausal women (n=1,192; P=.02). The T allele was associated with a lower BMI in the GIANT study, with each copy of the T allele reducing BMI by 0.02 SD unit (P=.01).

“The discovery of other genes influencing obesity in psychiatric populations and future prospective, controlled studies in psychiatric patients with (pharmaco)genetic tests are needed to individualize the clinical care and pharmacological treatment,” Eap said.

Disclosure: A grant from GlaxoSmithKline helped fund the CoLaus study. See the study for a full list of the researchers’ disclosures.