Association study of candidate genes with obesity and metabolic traits in antipsychotic-treated patients with first-episode psychosis over a 2-year period
Restricted accessResearch articleFirst published online May, 2020
Association study of candidate genes with obesity and metabolic traits in antipsychotic-treated patients with first-episode psychosis over a 2-year period
Patients with a first episode of psychosis (FEP) often display different metabolic disturbances even independently of drug therapy. However, antipsychotic (AP) treatment, especially with second-generation APs, is strongly linked to weight gain, which increases patients’ risk of developing obesity and other metabolic diseases. There is an important genetic risk component that can contribute to the appearance of these disturbances. The aim of the present study was to evaluate the effect of polymorphisms in selected candidate genes on obesity and other anthropometric and metabolic traits in 320 AP-treated FEP patients over the course of a 2-year follow-up.
Methods:
These patients were recruited in the multicentre PEPs study (Phenotype−genotype and environmental interaction; Application of a predictive model in first psychotic episodes). A total of 127 validated single nucleotide polymorphisms (SNPs) in 18 candidate genes were included in the genetic analysis.
Results:
After Bonferroni correction, SNPs in ADRA2A, FTO, CNR1, DRD2, DRD3, LEPR and BDNF were associated with obesity, abdominal circumference, triglycerides, HDL cholesterol, and/or percentage of glycated haemoglobin.
Conclusions:
Although our results should be interpreted as exploratory, they support previous evidence of the impact of these candidate genes on obesity and metabolic status. Further research is required to gain a better knowledge of the genetic variants that can be considered relevant metabolic risk factors. The ability to identify FEP patients at higher risk for these metabolic disturbances would enable clinicians to better select and control their AP treatment.
AllisonDBCaseyDE (2001) Antipsychotic-induced weight gain: A review of the literature. J Clin Psychiatry62(Suppl 7): 22–31.
2.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders. 4th ed.Washington, DC: American Psychiatric Press.
3.
ArangoCGiraldezMMerchan-NaranjoJ, et al. (2014) Second-generation antipsychotic use in children and adolescents: A six month prospective cohort study in drug-naive patients. J Am Acad Child Adolesc Psychiatry53: 1179–1190.
4.
BayeTMZhangYSmithE, et al. (2008) Genetic variation in cannabinoid receptor 1 (CNR1) is associated with derangements in lipid homeostasis, independent of body mass index. Pharmacogenomics9: 1647–1656.
5.
BenzinouMChèvreJCWardKJ, et al. (2008) Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations. Hum Mol Genet17: 1916–1921.
6.
BernardoMBioqueMCabreraB, et al.; PEPs Group (2017) Modelling gene-environment interaction in first episode of psychosis. Schizophr Res189: 181–189.
7.
BernardoMBioqueMParelladaM, et al.; PEPs Group (2013) Assessing clinical and functional outcomes in a gene-environment interaction study in first episode of psychosis (PEPs). Rev Psiquiatr Salud Ment6: 4–16.
8.
BioqueMGarcía-PortillaMAPGarcía-RizoC, et al.; PEPs Group (2018) Evolution of metabolic risk factors over a two-year period in a cohort of first episodes of psychosis. Schizophr Res193: 188–196.
9.
BlumKThanosPKGoldMS (2014) Dopamine and glucose, obesity, and reward deficiency syndrome. Front Psychol5: 919.
10.
BonaccorsoSSodhiMLiJ, et al. (2015) The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia. Bipolar Disord17: 528–535.
11.
ChangTTChenSLChangYH, et al. (2016) The DRD3 Ser9Gly polymorphism predicted metabolic change in drug-naive patients with bipolar II disorder. Medicine (Baltimore)95: e3488.
12.
ChenXLiuLHeW, et al. (2013) Association of the ADRA2A polymorphisms with the risk of type 2 diabetes: A meta-analysis. Clin Biochem46: 722–726.
13.
ChenPSYangYKYehTL, et al. (2008) Correlation between body mass index and striatal dopamine transporter availability in healthy volunteers—a SPECT study. Neuroimage40: 275–279.
14.
ClarkDSkrobotOAAdebiyiI, et al. (2009) Apolipoprotein-E gene variants associated with cardiovascular risk factors in antipsychotic recipients. Eur Psychiatry24: 456–463.
15.
CretaEFabbriCSerrettiA (2015) Genetics of second-generation antipsychotic and mood stabilizer-induced weight gain in bipolar disorder: Common and specific effects of key regulators of fat-mass homoeostasis genes. Pharmacogenet Genomics25: 354–362.
16.
de LuisDAFernández OvalleHIzaolaO, et al. (2018) RS 10767664 gene variant in Brain Derived Neurotrophic Factor (BDNF) affect metabolic changes and insulin resistance after a standard hypocaloric diet. J Diabetes Complications32: 216–220.
17.
Fernandez-EgeaEMillerBGarcia-RizoC, et al. (2011) Metabolic effects of olanzapine in patients with newly diagnosed psychosis. J Clin Psy- chopharmacol31: 154–159.
18.
FirstMGibbonMSpitzerR, et al. (1997) Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II). Washington, DC: American Psychiatry Publishing, Inc.
19.
FirstMSpitzerRGibbonM, et al. (1994) Structured Clinical Interview for DSM-IV Axis I Disorders - Administration Booklet. Washington, DC: American Psychiatric Press Inc.
20.
FirstMSpitzerRGibbonM, et al. (1999a) Entrevista clínica estructurada para los trastornos del eje-I del DSM-IV. Barcelona: Masson.
21.
FirstMSpitzerRGibbonM, et al. (1999b) SCID-II: guía del usuario para la entrevista clínica estructurada para los trastornos de la personalidad. Barcelona: Masson.
22.
FleischhackerWWSiuCOBodenR, et al. (2013) Metabolic risk factors in first-episode schizophrenia: Baseline prevalence and course analysed from the European first-episode schizophrenia trial. Int J Neuropsychopharmacol16: 987–995.
23.
FranciscoVPinoJCampos-CabaleiroV, et al. (2018) Obesity, fat mass and immune system: Role for leptin. Front Physiol9: 640.
24.
FraylingTMTimpsonNJWeedonMN, et al. (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science316: 889–894.
25.
GardnerDMMurphyALO’DonnellH, et al. (2010) International consensus study of antipsychotic dosing. Am J Psychiatry167: 686–693.
26.
GarencCPérusseLChagnonYC, et al. (2002) The alpha 2-adrenergic receptor gene and body fat content and distribution: The HERITAGE Family Study. Mol Med8: 88–94.
27.
GebhardtSTheisenFMHaberhausenM, et al. (2010) Body weight gain induced by atypical antipsychotics: An extension of the monozygotic twin and sib pair study. J Clin Pharm Ther35: 207–211.
28.
GregoorJGvan der WeideJLooversHM, et al. (2010) Association between LEP and LEPR gene polymorphisms and dyslipidemia in patients using atypical antipsychotic medication. Psychiatr Genet20: 311–316.
29.
GregoorJGvan der WeideJLooversHM, et al. (2011) Polymorphisms of the LEP, LEPR and HTR2C gene: obesity and BMI change in patients using antipsychotic medication in a naturalistic setting. Pharmacogenomics12: 919–923.
30.
GressierFPorcelliSCalatiR, et al. (2016) Pharmacogenetics of clozapine response and induced weight gain: A comprehensive review and meta-analysis. Eur Neuropsychopharmacol26: 163–185.
31.
HamdiAPorterJPrasadC (1992) Decreased striatal D2 dopamine receptors in obese Zucker rats: Changes during aging. Brain Res589: 338–340.
HoneaRACruchagaCPereaRD, et al.; Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2013). Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer’s disease neurodegeneration. PLoS One8: e76001.
34.
HongCJChenTTBaiYM, et al. (2012) Impact of apolipoprotein A5 (APOA5) polymorphisms on serum triglyceride levels in schizophrenic patients under long-term atypical antipsychotic treatment. World J Biol Psychiatry13: 22–29.
35.
JönssonEGNöthenMMGrünhageF, et al. (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry4: 290–296.
36.
KaoACMüllerDJ (2013) Genetics of antipsychotic-induced weight gain: Update and current perspectives. Pharmacogenomics14: 2067–2083.
37.
KaufmanJBirmaherBBrentD, et al. (1997) Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data. J Am Acad Child Adolesc Psychiatry36: 980–988.
38.
KocabasNAAntonijevicIFaghelC, et al. (2011). Brain-derived neurotrophic factor gene polymorphisms: Influence on treatment response phenotypes of major depressive disorder. Int Clin Psychopharmacol26: 1–10.
39.
LångbergECSeed AhmedMEfendicS, et al. (2013) Genetic association of adrenergic receptor alpha 2A with obesity and type 2 diabetes. Obesity (Silver Spring)21: 1720–1725.
40.
LebrunBBariohayBMoyseE, et al. (2006) Brain-derived neurotrophic factor (BDNF) and food intake regulation: A minireview. Auton Neurosci126–127: 30–38.
41.
LenczTRobinsonDGNapolitanoB, et al. (2010) DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet Genomics20: 569–572.
42.
MacNeilRRMüllerDJ (2016) Genetics of common antipsychotic-induced adverse effects. Mol Neuropsychiatry2: 61–78.
43.
MalhotraAKCorrellCUChowdhuryNI, et al. (2012) Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry69: 904–912.
44.
McEvoyJPMeyerJMGoffDC, et al. (2005) Prevalence of the metabolic syndrome in patients with schizophrenia: Baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res80: 19–32.
45.
MonteleonePMilanoWPetrellaC, et al. (2010) Endocannabinoid Pro129Thr FAAH functional polymorphism but not 1359G/A CNR1 polymorphism is associated with antipsychotic-induced weight gain. J Clin Psychopharmacol30: 441–445.
46.
NordentoftMWahlbeckKHallgrenJ, et al. (2013) Excess mortality, causes of death and life expectancy in 270,770 patients with recent onset of mental disorders in Denmark, Finland and Sweden. PLoS One8: e55176.
47.
ParkYMLeeSHLeeHJ, et al. (2013) Association between BDNF gene polymorphisms and serotonergic activity using loudness dependence of auditory evoked potentials in healthy subjects. PLoS One8: e60340.
48.
PerkinsDOLesermanJJarskogLF, et al. (2000) Characterizing and dating the onset of symptoms in psychotic illness: The Symptom Onset in Schizophrenia (SOS) inventory. Schizophr Res44: 1–10.
49.
PhillipsCMGoumidiLBertraisS, et al. (2010). Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults. J Nutr140: 238–244.
50.
PintoJAFFreitasPHBNunesFDD, et al. (2018) Prevalence of polymorphisms in the ANKK1, DRD2, DRD3 genes and metabolic syndrome in refractory schizophrenia. Rev Lat Am Enfermagem26: e2983.
51.
RealEGratacòsMSoriaV, et al. (2009) A brain-derived neurotrophic factor haplotype is associated with therapeutic response in obsessive-compulsive disorder. Biol Psychiatry66: 674–680.
52.
ReynoldsGPYevtushenkoOOGordonS, et al. (2013) The obesity risk gene FTO influences body mass in chronic schizophrenia but not initial antipsychotic drug-induced weight gain in first-episode patients. Int J Neuropsychopharmacol16: 1421–1425.
53.
RoerigJLSteffenKJMitchellJE (2011) Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs25: 1035–1059.
54.
RoffeeiSNMohamedZReynoldsGP, et al. (2014) Association of FTO, LEPR and MTHFR gene polymorphisms with metabolic syndrome in schizophrenia patients receiving antipsychotics. Pharmacogenomics15: 477–485.
55.
RussoPStrazzulloPCappuccioFP, et al. (2007) Genetic variations at the endocannabinoid type 1 receptor gene (CNR1) are associated with obesity phenotypes in men. J Clin Endocrinol Metab92: 2382–2386.
56.
ScuteriASannaSChenWM, et al. (2007) Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet3: e115.
SimonVCotaD (2017) Mechanisms in endocrinology: Endocannabinoids and metabolism: Past, present and future. Eur J Endocrinol176: R309–R324.
59.
SmithRCSegmanRHGolcer-DubnerT, et al. (2008) Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. Pharmacogenomics J8: 228–236.
60.
SongXPangLFengY, et al. (2014) Fat-mass and obesity-associated gene polymorphisms and weight gain after risperidone treatment in first episode schizophrenia. Behav Brain Funct10: 35.
61.
ThorleifssonGWaltersGBGudbjartssonDF, et al. (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet41: 18–24.
62.
TiwariAKZaiCCLikhodiO, et al. (2010) A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia. Neuropsychopharmacology35: 1315–1324.
63.
TiwariHKPatkiALiebermanJ, et al. (2011) Association of allelic variation in genes mediating aspects of energy homeostasis with weight gain during administration of antipsychotic drugs (CATIE Study). Front Genet2: 56.
64.
Totomoch-SerraAMuñozMLBurgueñoJ, et al. (2018) The ADRA2A rs553668 variant is associated with type 2 diabetes and five variants were associated at nominal significance levels in a population-based case-control study from Mexico City. Gene669: 28–34.
65.
TungYCAyusoEShanX, et al. (2010) Hypothalamic-specific manipulation of Fto, the ortholog of the human obesity gene FTO, affects food intake in rats. PLoS One5: e8771.
66.
van BaakMA (2001) The peripheral sympathetic nervous system in human obesity. Obes Rev2: 3–14.
67.
VanevskiFXuB (2013) Molecular and neural bases underlying roles of BDNF in the control of body weight. Front Neurosci7: 37.
68.
VenturaJLibermanRPGreenMF, et al. (1998) Training and quality assurance with the Structured Clinical Interview for DSM-IV (SCID-I/P). Psychiatry Res79: 163–173.
69.
WasimMAwanFRNajamSS, et al. (2016) Role of leptin deficiency, inefficiency, and leptin receptors in obesity. Biochem Genet54: 565–572.
70.
YangMMWangJFanJJ, et al. (2016) Variations in the obesity gene “LEPR” contribute to risk of type 2 diabetes mellitus: Evidence from a meta-analysis. J Diabetes Res2016: 5412084.
71.
ZhangJPLenczTZhangRX, et al. (2016) Pharmacogenetic associations of antipsychotic drug-related weight gain: A systematic review and meta-analysis. Schizophr Bull42: 1418–1437.
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