Association of CRTC1 polymorphisms with obesity markers in subjects from the general population with lifetime depression

Highlights

• Psychiatric disorders may share common etiological pathways with obesity.

• CRTC1 polymorphisms were not associated with major depression disorder (MDD) in three case-control samples with MDD.

• In PsyCoLaus, CRTC1 rs6510997C>T was significantly associated with lower fat mass in females but not in males.

• In PsyCoLaus, CRTC1 rs6510997C>T was significantly associated with lower fat mass in subjects with MDD but not in controls.

• CRTC1 polymorphisms seem to play a role with obesity markers only in individuals with MDD but not in non-depressive subjects.

Abstract

Background

Psychiatric disorders have been hypothesized to share common etiological pathways with obesity, suggesting related neurobiological bases. We aimed to examine whether CRTC1 polymorphisms were associated with major depressive disorder (MDD) and to test the association of these polymorphisms with obesity markers in several large case-control samples with MDD.

Methods

The association between CRTC1 polymorphisms and MDD was investigated in three case-control samples with MDD (PsyCoLaus n₁=3,362, Radiant n₂=3,148 and NESDA/NTR n₃=4,663). The effect of CRTC1 polymorphisms on obesity markers was then explored.

Results

CRTC1 polymorphisms were not associated with MDD in the three samples. CRTC1 rs6510997C>T was significantly associated with fat mass in the PsyCoLaus study. In fact, a protective effect of this polymorphism was found in MDD cases (n=1,434, β=−1.32%, 95% CI −2.07 to −0.57, p<0.001), but not in controls. In the Radiant study, CRTC1 polymorphisms were associated with BMI, exclusively in individuals with MDD (n=2,138, β=−0.75 kg/m², 95% CI −1.30 to −0.21, p=0.007), while no association with BMI was found in the NESDA/NTR study.

Limitations

Estimated fat mass using bioimpedance that capture more accurately adiposity was only present in the PsyCoLaus sample.

Conclusions

CRTC1 polymorphisms seem to play a role with obesity markers in individuals with MDD rather than non-depressive individuals. Therefore, the weak association previously reported in the population-based samples was driven by cases diagnosed with lifetime MDD. However, CRTC1 seems not to be implicated directly in the development of psychiatric diseases.

Introduction

Based on a growing body of evidence, it has been hypothesized that psychiatric disorders, such as schizophrenia and mood disorders, are causally related to or share common etiological pathways with obesity, suggesting that comorbid obesity and psychiatric disorders have related neurobiological bases (Farmer et al., 2008, Forty et al., 2014). Increased appetite, weight gain and obesity are common symptoms of depression (Blaine, 2008, Luppino et al., 2010). On the other hand, obese individuals were also found to have higher prevalence of depression (Luppino et al., 2010). Shared genetic factors were previously suggested (Afari et al., 2010, Comings et al., 1996, Rivera et al., 2012, Samaan et al., 2013), however, due to the pathological complexity of both conditions and the polygenic factors affecting them, many genetic factors are still to unravel. Additionally, due to heterogeneity of depression, genetic association studies could give conflicting results. One example is the fat mass and obesity-associated gene (FTO) for which the common rs9939609-A variant previously associated with increased body mass index (BMI) and obesity in several studies (Frayling et al., 2007, Qi et al., 2008, Scuteri et al., 2007) was shown to be negatively associated with depression in a meta-analysis of four large studies (Samaan et al., 2013). On the other hand, the same variant was found to be positively associated with depression in a recent large case-control study (Milaneschi et al., 2014), but this association was entirely driven by the atypical depression subtype (subtype characterized typically by increased appetite, weight gain and hypersomnia).

We previously showed an association between a coding single nucleotide polymorphism (SNP) within the CREB-regulated transcription coactivator 1 (CRTC1) gene (rs3746266A>G) and BMI in 3 independent psychiatric samples (brief description of these samples is given in the Supplementary data and is described in details in ref (Choong et al., 2013)). Carriers of the rs3746266-G variant showed significantly protective effect against obesity compared to non-carriers. The sex-stratified analysis in the 3 combined psychiatric samples showed a protective effect for the G allele both in men and women. However, the strongest and most clinically relevant association was observed in women younger than 45 years old. Although the effect was weaker, we also found a protective effect of the T allele of the CRTC1 rs6510997C>T (a proxy of rs3746266A>G, r²=0.7) on fat accumulation in a large population-based sample (CoLaus), with the strongest association again in premenopausal women (Choong et al., 2013).

In animal models, we previously showed that mice lacking CRTC1 exhibit neurobehavioral endophenotypes related to mood disorders, depression-related behavior and a blunted behavioral response to antidepressants (Breuillaud et al., 2012). Crtc1 knockout mice also developed obese features, including obesity-related metabolic complications, under normal diets (Altarejos et al., 2008, Breuillaud et al., 2009). Altogether, these findings suggest that the Crtc1 gene might play a common role in obesity and depression-related behavior.

In the present study, we aimed to examine whether CRTC1 SNPs are associated with major depressive disorder (MDD), and to test the association of CRTC1 SNPs with obesity markers in several large case-control samples with MDD. The same CRTC1 SNPs (rs3746266A>G and rs6510997C>T) investigated previously (Choong et al., 2013) were used in the current study.