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Original Investigation |

Influence of CRTC1 Polymorphisms on Body Mass Index and Fat Mass in Psychiatric Patients and the General Adult Population

Eva Choong, PharmD, PhD1; Lina Quteineh, MD, PhD1; Jean-René Cardinaux, PhD2,3; Mehdi Gholam-Rezaee, PhD4; Frederik Vandenberghe, PharmD, MSc1; Maria Dobrinas, PharmD, PhD1; Guido Bondolfi, MD5; Manuela Etter, MD5; Laurent Holzer, MD3; Pierre Magistretti, MD, PhD2,6; Armin von Gunten, MPhil, MD7; Martin Preisig, MD, MPH4; Peter Vollenweider, MD8; Jacques S. Beckmann, PhD9,10; François P. Pralong, MD11; Gerard Waeber, MD8; Zoltan Kutalik, PhD9,12; Philippe Conus, MD13; Murielle Bochud, MD, PhD14; Chin B. Eap, PhD1,15; for the ODEX team
[+] Author Affiliations
1Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland
2Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland
3Child and Adolescent Psychiatric Clinic, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland
4Centre of Psychiatric Epidemiology and Psychopathology, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland
5Department of Mental Health and Psychiatry, University Hospital of Geneva, Geneva, Switzerland
6Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
7Service of Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland
8Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
9Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
10Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland
11Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
12Swiss Institute of Bioinformatics, Lausanne, Switzerland
13Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland
14Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
15School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
JAMA Psychiatry. 2013;70(10):1011-1019. doi:10.1001/jamapsychiatry.2013.187.
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Importance  There is a high prevalence of obesity in psychiatric patients, possibly leading to metabolic complications and reducing life expectancy. The CREB-regulated transcription coactivator 1 (CRTC1) gene is involved in energy balance and obesity in animal models, but its role in human obesity is unknown.

Objective  To determine whether polymorphisms within the CRTC1 gene are associated with adiposity markers in psychiatric patients and the general population.

Design, Setting, and Participants  Retrospective and prospective data analysis and population-based samples at Lausanne and Geneva university hospitals in Switzerland and a private clinic in Lausanne, Switzerland. The effect of 3 CRTC1 polymorphisms on body mass index (BMI) and/or fat mass was investigated in a discovery cohort of psychiatric outpatients taking weight gain–inducing psychotropic drugs (sample 1, n = 152). The CRTC1 variant that was significantly associated with BMI and survived Bonferroni corrections for multiple comparison was then replicated in 2 independent psychiatric samples (sample 2, n = 174 and sample 3, n = 118) and 2 white population-based samples (sample 4, n = 5338 and sample 5, n = 123 865).

Intervention  Noninterventional studies.

Main Outcome and Measure  Difference in BMI and/or fat mass between CRTC1 genotype groups.

Results  Among the CRTC1 variants tested in the first psychiatric sample, only rs3746266A>G was associated with BMI (Padjusted = .003). In the 3 psychiatric samples, carriers of the rs3746266 G allele had a lower BMI than noncarriers (AA genotype) (sample 1, P = .001; sample 2, P = .05; and sample 3, P = .0003). In the combined analysis, excluding patients taking other weight gain–inducing drugs, G allele carriers (n = 98) had a 1.81–kg/m2 lower BMI than noncarriers (n = 226; P < .0001). The strongest association was observed in women younger than 45 years, with a 3.87–kg/m2 lower BMI in G allele carriers (n = 25) compared with noncarriers (n = 48; P < .0001), explaining 9% of BMI variance. In the population-based samples, the T allele of rs6510997C>T (a proxy of the rs3746266 G allele; r2 = 0.7) was associated with lower BMI (sample 5, n = 123 865; P = .01) and fat mass (sample 4, n = 5338; P = .03). The strongest association with fat mass was observed in premenopausal women (n = 1192; P = .02).

Conclusions and Relevance  These findings suggest that CRTC1 contributes to the genetics of human obesity in psychiatric patients and the general population. Identification of high-risk subjects could contribute to a better individualization of the pharmacological treatment in psychiatry.

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