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Molecular pathway analysis associates alterations in obesity-related genes and antipsychotic-induced weight gain

Published online by Cambridge University Press:  14 November 2019

Henrik Thyge Corfitsen Open the ORCID record for Henrik Thyge Corfitsen [Opens in a new window] ,
Betina Krantz ,
Agnete Larsen  and
Antonio Drago Open the ORCID record for Antonio Drago [Opens in a new window]
Henrik Thyge Corfitsen*
Affiliation:
Institute for Biomedicin, Aarhus University, Psykiatrisk Forskningsenhed Vest, Herning, Denmark
Betina Krantz
Affiliation:
VIA University College, Holstebro, Denmark
Agnete Larsen
Affiliation:
Institute for Biomedicin, Forskning og uddannelse, Aarhus University, Øst, Denmark
Antonio Drago
Affiliation:
Institute for Biomedicin, Aarhus University, Psykiatrisk Forskningsenhed Vest, Herning, Denmark
*
Author for correspondence: Henrik Thyge Corfitsen, Email: [email protected]
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Abstract

Objective:

Antipsychotics often induce excessive weight gain. We hypothesised that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain (AIWG). This hypothesis was tested in a subset of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial data set.

Methods:

The CATIE trial compared effects and side effects of five different antipsychotics through an 18-month period. Based on the maximum weight gain recorded, excessive weight gain was defined as >7% weight gain. Cytoscape and GeneMANIA were instrumental in composing a molecular pathway from eight selected genes linked to obesity. Genetic information on a total of 495.172 single-nucleotide polymorphisms (SNPs) were available from 765 (556 males) individuals. Enrichment test was conducted through ReactomePA and Bioconductor. A permutation test was performed, testing the generated pathway against 105 permutated pathways (p ≤ 0.05). In addition, a standard genome-wide association study (GWAS) analysis was performed.

Result:

GWAS analysis did not detect significant differences related to excessive weight gain. The pathway generated contained 28 genes. A total of 2067 SNPs were significantly expressed (p < 0.01) within this pathway when comparing excessive weight gainers to the rest of the sample. Affected genes including PPARG and PCSK1 were not previously related to treatment-induced weight gain.

Conclusions:

The molecular pathway composed from high-risk obesity genes was shown to overlap with genetics of patients who gained >7% weight gain during the CATIE trial. This suggests that genes related to obesity compose a pathway of increased risk of excessive AIWG. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.

Keywords

antipsychotic agentsmetabolic networks and pathwayspharmacogeneticspolymorphismsingle nucleotideweight gain
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 32 , Issue 2 , April 2020 , pp. 72 - 83
Copyright
© Scandinavian College of Neuropsychopharmacology 2019

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References

Adolph, TE, Grander, C, Grabherr, F and Tilg, H (2017) Adipokines and non-alcoholic fatty liver disease: multiple interactions. International Journal of Molecular Sciences 18, pii: E1649.CrossRefGoogle ScholarPubMed
Aulchenko, YS, Ripke, S, Isaacs, A and van Duijn, CM (2007) GenABEL: an R library for genome-wide association analysis. Bioinformatics (Oxford, England) 23, 1294–1296.CrossRefGoogle Scholar
Bak, M, Fransen, A, Janssen, J, van Os, J and Drukker, M (2014) Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE 9, e94112.CrossRefGoogle ScholarPubMed
Bordoni, L, Marchegiani, F, Piangerelli, M, Napolioni, V and Gabbianelli, R (2017) Obesity-related genetic polymorphisms and adiposity indices in a young Italian population. International Union of Biochemistry and Molecular Biology Life 69, 98–105.CrossRefGoogle Scholar
Brandl, EJ, Frydrychowicz, C, Tiwari, AK, Lett, TA, Kitzrow, W, Büttner, S, Ehrlich, S, Meltzer, HY, Lieberman, JA, Kennedy, JL, Müller, DJ and Puls, I (2012). Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain. Progress in Neuro-Psychopharmacology and Biological Psychiatry 38, 134–141.CrossRefGoogle ScholarPubMed
Brandl, EJ, Tiwari, AK, Zai, CC, Chowdhury, NI, Lieberman, JA, Meltzer, HY, Kennedy, JL and Müller, DJ (2014) No evidence for a role of the peroxisome proliferator-activated receptor gamma (PPARG) and adiponectin (ADIPOQ) genes in antipsychotic-induced weight gain. Psychiatry Research 219, 255–260.CrossRefGoogle ScholarPubMed
Bressington, D, Mui, J, Tse, ML, Gray, R, Cheung, EFC and Chien, WT (2016) Cardiometabolic health, prescribed antipsychotics and health-related quality of life in people with schizophrenia-spectrum disorders: a cross-sectional study. BMC Psychiatry 16, 411.CrossRefGoogle ScholarPubMed
Catalano, S, Mauro, L, Bonofiglio, D, Pellegrino, M, Qi, H, Rizza, P, Vizza, D, Bossi, G and Andò, S (2011) In vivo and in vitro evidence that PPARγ ligands are antagonists of leptin signaling in breast cancer. American Journal of Pathology 179, 1030–1040.CrossRefGoogle ScholarPubMed
Choquet, H, Kasberger, J, Hamidovic, A and Jorgenson, E (2013) Contribution of common PCSK1 genetic variants to obesity in 8,359 subjects from multi-ethnic American population. PLoS ONE 8, e57857.CrossRefGoogle ScholarPubMed
Choquet, H and Meyre, D (2011) Genetics of obesity: what have we learned? Current Genomics 12, 169–179.CrossRefGoogle ScholarPubMed
Chowdhury, NI, Souza, RP, Tiwari, AK, Brandl, EJ, Sicard, M, Meltzer, HY, Lieberman, JA, Kennedy, JL and Müller, DJ (2014) Investigation of melanocortin system gene variants in antipsychotic-induced weight gain. The World Journal of Biological Psychiatry: The Official Journal of the World Federation Societies of Biological Psychiatry 15, 251–258.CrossRefGoogle ScholarPubMed
Chowdhury, NI, Tiwari, AK, Souza, RP, Zai, CC, Shaikh, SA, Chen, S, Liu, F, Lieberman, JA, Meltzer, HY, Malhotra, AK, Kennedy, JL and Müller, DJ (2013) Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene. The Pharmacogenomics Journal 13, 272–279.CrossRefGoogle ScholarPubMed
Correll, CU, Manu, P, Olshanskiy, V, Napolitano, B, Kane, JM and Malhotra, AK (2009) Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. The Journal of the American Medical Association 302, 1765–1773.CrossRefGoogle ScholarPubMed
Creemers, JWM, Choquet, H, Stijnen, P, Vatin, V, Pigeyre, M, Beckers, S, Meulemans, S, Than, ME, Yengo, L, Tauber, M, Balkau, B, Elliott, P, Jarvelin, MR, Van Hul, W, Van Gaal, L, Horber, F, Pattou, F, Froguel, P and Meyre, D (2012) Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity. Diabetes 61, 383–390.CrossRefGoogle ScholarPubMed
Creta, E, Fabbri, C and Serretti, A (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. Pharmacogenetics and Genomics 25, 354–362.CrossRefGoogle ScholarPubMed
Cuerda, C, Merchan-Naranjo, J, Velasco, C, Gutierrez, A, Leiva, M, de Castro, MJ, Parellada, M, Giráldez, M, Bretón, I, Camblor, M, García-Peris, P, Dulín, E, Sanz, I, Desco, M and Arango, C (2011) Influence of resting energy expenditure on weight gain in adolescents taking second-generation antipsychotics. Clinical Nutrition (Edinburgh, Scotland) 30, 616–623.CrossRefGoogle ScholarPubMed
Czerwensky, F, Leucht, S and Steimer, W (2013a) Association of the common MC4R rs17782313 polymorphism with antipsychotic-related weight gain. Journal of Clinical Psychopharmacology 33, 74–79.CrossRefGoogle ScholarPubMed
Czerwensky, F, Leucht, S and Steimer, W (2013b) MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain? The International Journal of Neuropsychopharmacology 16, 2103–2109.CrossRefGoogle ScholarPubMed
Dang, Y-F, Jiang, X-N, Gong, F-L and Guo, X-L (2018) New insights into molecular mechanisms of rosiglitazone in monotherapy or combination therapy against cancers. Chemico-Biological Interactions 296, 162–170.CrossRefGoogle ScholarPubMed
Day, R, Schafer, MK, Watson, SJ, Chrétien, M and Seidah, NG (1992) Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary. Molecular Endocrinology (Baltimore, Md.) 6, 485–497.Google ScholarPubMed
Doudney, K, Harley, JA, Pearson, JF, Miller, A, Aitchison, A, Kennedy, MA, Porter, RJ, Elmslie, JL and Joyce, PR (2009) Upstream genetic variant near INSIG2, influences response to carnitine supplementation in bipolar patients with valproate-induced weight gain. Acta Neuropsychiatrica 21, 133–140.CrossRefGoogle ScholarPubMed
Doulla, M, McIntyre, AD, Hegele, RA and Gallego, PH (2014) A novel MC4R mutation associated with childhood-onset obesity: a case report. Paediatrics & Child Health 19, 515–518.CrossRefGoogle ScholarPubMed
Drost, H-G and Paszkowski, J (2017) Biomartr: genomic data retrieval with R. Bioinformatics (Oxford, England) 33, 1216–1217.Google ScholarPubMed
Dubern, B and Clement, K (2012) Leptin and leptin receptor-related monogenic obesity. Biochimie 94, 2111–2115.CrossRefGoogle ScholarPubMed
Dušátková, L, Zamrazilová, H, Aldhoon Hainerová, I, Atkinson, RL, Sedláčková, B, Lee, ZP, Včelák, J, Bendlová, B, Kunešová, M and Hainer, V (2015) Association of adenovirus 36 infection with obesity-related gene variants in adolescents. Physiological Research 2(Suppl. 64), S197–S202.Google Scholar
Ehrlich, S, Leopold, K, Merle, JV, Theophil, I, Haag, W, Lautenschlager, M and Schaefer, M (2012) Trajectories of agouti-related protein and leptin levels during antipsychotic-associated weight gain in patients with schizophrenia. Journal of Clinical Psychopharmacology 32, 767–772.CrossRefGoogle ScholarPubMed
Ellingrod, VL, Bishop, JR, Moline, J, Lin, Y-C and Miller, DD (2007) Leptin and leptin receptor gene polymorphisms and increases in body mass index (BMI) from olanzapine treatment in persons with schizophrenia. Psychopharmacology Bulletin 40, 57–62.Google ScholarPubMed
Enns, JE, Taylor, CG and Zahradka, P (2011) Variations in adipokine genes AdipoQ, Lep, and LepR are associated with risk for obesity-related metabolic disease: the modulatory role of gene-nutrient interactions. Journal of Obesity 2011, 168659.CrossRefGoogle ScholarPubMed
Erez, G, Tirosh, A, Rudich, A, Meiner, V, Schwarzfuchs, D, Sharon, N, Shpitzen, S, Blüher, M, Stumvoll, M, Thiery, J, Fiedler, GM, Friedlander, Y, Leiterstdorf, E and Shai, I (2011) Phenotypic and genetic variation in leptin as determinants of weight regain. International Journal of Obesity 2005 35, 785–792.CrossRefGoogle ScholarPubMed
Fernø, J, Varela, L, Skrede, S, Vázquez, MJ, Nogueiras, R, Diéguez, C, Vidal-Puig, A, Steen, VM and López, M (2011) Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation. PLoS ONE 6, e20571.CrossRefGoogle ScholarPubMed
Franks, PW, Jablonski, KA, Delahanty, L, Hanson, RL, Kahn, SE, Altshuler, D, Knowler, WC, Florez, JC and Diabetes Prevention Program Research Group (2007) The Pro12Ala variant at the peroxisome proliferator-activated receptor gamma gene and change in obesity-related traits in the Diabetes Prevention Program. Diabetologia 50, 2451–2460.CrossRefGoogle ScholarPubMed
Frayling, TM, Timpson, NJ, Weedon, MN, Zeggini, E, Freathy, RM, Lindgren, CM, Perry, JR, Elliott, KS, Lango, H, Rayner, NW, Shields, B, Harries, LW, Barrett, JC, Ellard, S, Groves, CJ, Knight, B, Patch, AM, Ness, AR, Ebrahim, S, Lawlor, DA, Ring, SM, Ben-Shlomo, Y, Jarvelin, MR, Sovio, U, Bennett, AJ, Melzer, D, Ferrucci, L, Loos, RJ, Barroso, I, Wareham, NJ, Karpe, F, Owen, KR, Cardon, LR, Walker, M, Hitman, GA, Palmer, CN, Doney, AS, Morris, AD, Smith, GD, Hattersley, AT and McCarthy, MI (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894.CrossRefGoogle ScholarPubMed
Fredriksson, R, Hägglund, M, Olszewski, PK, Stephansson, O, Jacobsson, JA, Olszewska, AM, Levine, AS, Lindblom, J and Schiöth, HB (2008) The obesity gene, FTO, Is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology 149, 2062–2071.CrossRefGoogle Scholar
Gaillard, R, Durmuş, B, Hofman, A, Mackenbach, JP, Steegers, EAP and Jaddoe, VWV (2013) Risk factors and outcomes of maternal obesity and excessive weight gain during pregnancy. Obesity (Silver Spring, Md.) 21, 1046–1055.CrossRefGoogle ScholarPubMed
Gregoor, JG, van der Weide, J, Loovers, HM, van Megen, HJGM, Egberts, TCG and Heerdink, ER (2011) Polymorphisms of the LEP, LEPR and HTR2C gene: obesity and BMI change in patients using antipsychotic medication in a naturalistic setting. Pharmacogenomics 12, 919–923.CrossRefGoogle Scholar
Gregoor, JG, van der Weide, J, Mulder, H, Cohen, D, van Megen, HJGM, Egberts, ACG and Heerdink, ER (2009) Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication. Journal of Clinical Psychopharmacology 29, 21–25.CrossRefGoogle ScholarPubMed
Hardy, R, Wills, AK, Wong, A, Elks, CE, Wareham, NJ, Loos, RJF, Kuh, D and Ong, KK (2010) Life course variations in the associations between FTO and MC4R gene variants and body size. Human Molecular Genetics 19, 545–552.CrossRefGoogle ScholarPubMed
Hart Sailors, ML, Folsom, AR, Ballantyne, CM, Hoelscher, DM, Jackson, AS, Linda Kao, WH, Pankow, JS and Bray, MS (2007) Genetic variation and decreased risk for obesity in the Atherosclerosis Risk in Communities Study. Diabetes Obesity and Metabolism 9, 548–557.CrossRefGoogle ScholarPubMed
Hasan, AU, Ohmori, K, Konishi, K, Igarashi, J, Hashimoto, T, Kamitori, K, Yamaguchi, F, Tsukamoto, I, Uyama, T, Ishihara, Y, Noma, T, Tokuda, M and Kohno, M (2015) Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPARγ mediated pathways in 3T3-L1 adipocytes. Molecular and Cellular Endocrinology 406, 10–18.CrossRefGoogle ScholarPubMed
Helwig, M, Vivoli, M, Fricker, LD and Lindberg, I (2011) Regulation of neuropeptide processing enzymes by catecholamines in endocrine cells. Molecular Pharmacology 80, 304–313.CrossRefGoogle ScholarPubMed
Hetherington, MM and Cecil, JE (2010) Gene-environment interactions in obesity. Forum of Nutrition 63, 195–203.CrossRefGoogle ScholarPubMed
Hinney, A and Hebebrand, J (2008) Polygenic obesity in humans. Obesity Facts 1, 35–42.CrossRefGoogle ScholarPubMed
Huber, W, Carey, VJ, Gentleman, R, Anders, S, Carlson, M, Carvalho, BS, Bravo, HC, Davis, S, Gatto, L, Girke, T, Gottardo, R, Hahne, F, Hansen, KD, Irizarry, RA, Lawrence, M, Love, MI, MacDonald, J, Obenchain, V, Oleś, AK, Pagès, H, Reyes, A, Shannon, P, Smyth, GK, Tenenbaum, D, Waldron, L and Morgan, M (2015) Orchestrating high-throughput genomic analysis with Bioconductor. Nature Methods 12, 115–121.CrossRefGoogle ScholarPubMed
Ingelman‐Sundberg, M (2001). Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy. Journal of Internal Medicine 250, 186–200.CrossRefGoogle ScholarPubMed
Jassim, G, Fernø, J, Theisen, FM, Haberhausen, M, Christoforou, A, Håvik, B, Gebhardt, S, Remschmidt, H, Mehler-Wex, C, Hebebrand, J, Lehellard, S and Steen, VM (2011) Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia. Pharmacopsychiatry 44, 15–20.Google ScholarPubMed
Jeninga, EH, Gurnell, M and Kalkhoven, E (2009) Functional implications of genetic variation in human PPARgamma. Trends in Endocrinology and Metabolism 20, 380–387.CrossRefGoogle ScholarPubMed
Jiao, Y, Zhang, J, Lu, L, Xu, J and Qin, L (2016) The Fto gene regulates the proliferation and differentiation of pre-adipocytes in vitro. Nutrients 8, 102.CrossRefGoogle ScholarPubMed
Kang, S-G, Lee, H-J, Park, Y-M, Choi, J-E, Han, C, Kim, Y-K, Kim, SH, Lee, MS, Joe, SH, Jung, IK and Kim, L (2008) Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain. Progress in Neuro-Psychopharmacology and Biological Psychiatry 32, 160–163.CrossRefGoogle ScholarPubMed
Kang, SH, Lee, J, Han, HR, Soh, M and Hong, JP (2014) Polymorphisms of the leptin and HTR2C genes and clozapine-induced weight change and baseline BMI in patients with chronic schizophrenia. Psychiatric Genetics 24, 249–256.CrossRefGoogle ScholarPubMed
Kao, ACC and Müller, DJ (2013) Genetics of antipsychotic-induced weight gain: update and current perspectives. Pharmacogenomics 14, 2067–2083.CrossRefGoogle ScholarPubMed
Kasim, NB, Huri, HZ, Vethakkan, SR, Ibrahim, L and Abdullah, BM (2016) Genetic polymorphisms associated with overweight and obesity in uncontrolled Type 2 diabetes mellitus. Biomarkers in Medicine 10, 403–415.CrossRefGoogle ScholarPubMed
Klemettilä, J-P, Kampman, O, Seppälä, N, Viikki, M, Hämäläinen, M, Moilanen, E, Mononen, N, Lehtimäki, T and Leinonen, E (2015) Association study of the HTR2C, leptin and adiponectin genes and serum marker analyses in clozapine treated long-term patients with schizophrenia. European Psychiatry: The Journal of the European Psychiatry Association 30, 296–302.CrossRefGoogle ScholarPubMed
Koskinen, S, Kampman, O, Solismaa, A, Lyytikäinen, L-P, Seppälä, N, Viikki, M, Hämäläinen, M, Moilanen, E, Mononen, N, Lehtimäki, T and Leinonen, E (2016) INSIG2 polymorphism and weight gain, dyslipidemia and serum adiponectin in Finnish patients with schizophrenia treated with clozapine. Pharmacogenomics 17, 1987–1997.CrossRefGoogle ScholarPubMed
Krashes, MJ, Koda, S, Ye, C, Rogan, SC, Adams, AC, Cusher, DS, Maratos-Flier, E, Roth, BL and Lowell, BB (2011). Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. The Journal of Clinical Investigation 121, 1424–1428.CrossRefGoogle ScholarPubMed
Kredentser, MS, Martens, PJ, Chochinov, HM and Prior, HJ (2014) Cause and rate of death in people with schizophrenia across the lifespan: a population-based study in Manitoba, Canada. The Journal of Clinical Psychiatry 75, 154–161.CrossRefGoogle ScholarPubMed
Kulanuwat, S, Phonrat, B, Tungtrongchitr, A, Limwongse, C, Chongviriyaphan, N, Tungtrongchitr, R and Santiprabhob, J (2014) Effects of PCSK1 genetic variants on obesity among Thai children and their family members: in relation to health risk, and biochemical and anthropometric parameters. The Southeast Asian Journal of Tropical Medicine and Public Health 45, 214–225.Google ScholarPubMed
Kulanuwat, S, Santiprabhob, J, Phonrat, B, Limwongse, C, Tungtrongchitr, A, Chongviriyaphan, N and Tungtrongchitr, R (2015) Association between rs155971 in the PCSK1 gene and the lipid profile of obese Thai children: a family-based study. Genetics and Molecular Research 14, 9136–9144.CrossRefGoogle ScholarPubMed
Kursungoz, C, Ak, M and Yanik, T (2015) Effects of risperidone treatment on the expression of hypothalamic neuropeptide in appetite regulation in Wistar rats. Brain Research 1596, 146–155.CrossRefGoogle ScholarPubMed
Kvaløy, K, Holmen, J, Hveem, K and Holmen, TL (2015) Genetic effects on longitudinal changes from healthy to adverse weight and metabolic status – The HUNT study. PLoS ONE 10, e0139632.CrossRefGoogle ScholarPubMed
Le Hellard, S, Theisen, FM, Haberhausen, M, Raeder, MB, Fernø, J, Gebhardt, S, Hinney, A, Remschmidt, H, Krieg, JC, Mehler-Wex, C, Nöthen, MM, Hebebrand, J and Steen, VM (2009) Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects? Molecular Psychiatry 14, 308–317.CrossRefGoogle Scholar
Lett, TA, Wallace, TJM, Chowdhury, NI, Tiwari, AK, Kennedy, JL and Müller, DJ (2012) Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Molecular Psychiatry 17, 242–266.CrossRefGoogle ScholarPubMed
Li, H, Wang, X, Zhou, Y, Ni, G, Su, Q, Chen, Z, Chen, Z, Li, J, Chen, X, Hou, X, Xie, W, Xin, S, Zhou, L and Huang, M (2015) Association of LEPR and ANKK1 gene polymorphisms with weight gain in epilepsy patients receiving valproic acid. The International Journal of Neuropsychopharmacology 18, pyv021.CrossRefGoogle ScholarPubMed
Li, S, Xu, C, Tian, Y, Wang, X, Jiang, R, Zhang, M, Wang, L, Yang, G, Gao, Y, Song, C, He, Y, Zhang, Y, Li, J and Li, WD (2017) TOX and ADIPOQ gene polymorphisms are associated with antipsychotic-induced weight gain in Han Chinese. Scientific Reports 7, 45203.CrossRefGoogle ScholarPubMed
Lian, J, De Santis, M, He, M and Deng, C (2015) Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: the role of histaminergic and NPY pathways. Pharmacological Research 95–96, 20–26.CrossRefGoogle ScholarPubMed
Lieberman, JA, Stroup, TS, McEvoy, JP, Swartz, MS, Rosenheck, RA, Perkins, DO, Keefe, RS, Davis, SM, Davis, CE, Lebowitz, BD, Severe, J, Hsiao, JK and Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 353, 1209–1223.CrossRefGoogle ScholarPubMed
Löffler, D, Landgraf, K, Körner, A, Kratzsch, J, Kirkby, KC and Himmerich, H (2016) Modulation of triglyceride accumulation in adipocytes by psychopharmacological agents in vitro. Journal of Psychiatric Research 72, 37–42.CrossRefGoogle ScholarPubMed
Lotta, LA, Mokrosiński, J, Mendes de Oliveira, E, Li, C, Sharp, SJ, Luan, J, Brouwers, B, Ayinampudi, V, Bowker, N, Kerrison, N, Kaimakis, V, Hoult, D, Stewart, ID, Wheeler, E, Day, FR, Perry, JRB, Langenberg, C, Wareham, NJ and Farooqi, IS (2019) Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell 177, 597–607.e9.CrossRefGoogle ScholarPubMed
Lyche, JL, Nourizadeh-Lillabadi, R, Karlsson, C, Stavik, B, Berg, V, Skåre, JU, Alestrøm, P and Ropstad, E (2011) Natural mixtures of POPs affected body weight gain and induced transcription of genes involved in weight regulation and insulin signaling. Aquatic Toxicology (Amsterdam, Netherlands) 102, 197–204.CrossRefGoogle ScholarPubMed
MacNeil, RR and Müller, DJ (2016) Genetics of common antipsychotic-induced adverse effects. Molecular Neuropsychiatry 2, 61–78.CrossRefGoogle ScholarPubMed
Malhotra, AK, Correll, CU, Chowdhury, NI, Müller, DJ, Gregersen, PK, Lee, AT, Tiwari, AK, Kane, JM, Fleischhacker, WW, Kahn, RS, Ophoff, RA, Meltzer, HY, Lencz, T and Kennedy, JL (2012) Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Archives of Neurology & Psychiatry 69, 904–912.Google ScholarPubMed
Martins, MC, Trujillo, J, Farias, DR, Struchiner, CJ and Kac, G (2016) Association of the FTO (rs9939609) and MC4R (rs17782313) gene polymorphisms with maternal body weight during pregnancy. Nutrition (Burbank, Los Angel County, Calif.) 32, 1223–1230.CrossRefGoogle ScholarPubMed
McEvoy, JP, Lieberman, JA, Perkins, DO, Hamer, RM, Gu, H, Lazarus, A, Sweitzer, D, Olexy, C, Weiden, P and Strakowski, SD (2007) Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. American Journal of Psychiatry 164, 1050–1060.CrossRefGoogle ScholarPubMed
Miranda, RCK, Vetter, SB, Genro, JP, Campagnolo, PDB, Mattevi, VS, Vitolo, MR and Almeida, S (2015) SLC6A14 and 5-HTR2C polymorphisms are associated with food intake and nutritional status in children. Clinical Biochemistry 48, 1277–1282.CrossRefGoogle ScholarPubMed
Mou, X, Zhang, Z, Zhang, X, Shi, J and Sun, J (2008) -2548G/A functional polymorphism in the promoter region of leptin gene and antipsychotic agent-induced weight gain in schizophrenic patients: a study of nuclear family-based association. Journal of Central South University. Medical Sciences. Zhong Nan Da Xue Xue Bao Yi Xue Ban 33, 316–320.Google ScholarPubMed
Murray, CJL and Lopez, AD (1996) The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020 ; Summary. Cambridge: Harvard School of Public Health [u.a.]. 43 p. (Global burden of disease and injury series).Google Scholar
Nordang, GBN, Busk, ØL, Tveten, K, Hanevik, HI, Fell, AKM, Hjelmesæth, J, Holla, ØL and Hertel, JK (2017) Next-generation sequencing of the monogenic obesity genes LEP, LEPR, MC4R, PCSK1 and POMC in a Norwegian cohort of patients with morbid obesity and normal weight controls. Molecular Genetics and Metabolism 121, 51–56.CrossRefGoogle Scholar
Nurmi, EL, Spilman, SL, Whelan, F, Scahill, LL, Aman, MG, McDougle, CJ, Arnold, LE, Handen, B, Johnson, C, Sukhodolsky, DG, Posey, DJ, Lecavalier, L, Stigler, KA, Ritz, L, Tierney, E, Vitiello, B, McCracken, JT and Research Units on Pediatric Psychopharmacology Autism Network (2013) Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies. Translational Psychiatry 3, e274.CrossRefGoogle ScholarPubMed
Opgen-Rhein, C, Brandl, EJ, Müller, DJ, Neuhaus, AH, Tiwari, AK, Sander, T and Dettling, M (2010) Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics 11, 773–780.CrossRefGoogle Scholar
Oyarce, AM, Hand, TA, Mains, RE and Eipper, BA (1996) Dopaminergic regulation of secretory granule-associated proteins in rat intermediate pituitary. Journal of Neurochemistry 67, 229–241.CrossRefGoogle ScholarPubMed
Patel, JK, Buckley, PF, Woolson, S, Hamer, RM, McEvoy, JP, Perkins, DO, Lieberman, JA and CAFE Investigators (2009) Metabolic profiles of second-generation antipsychotics in early psychosis: findings from the CAFE study. Schizophrenia Research 111, 9–16.CrossRefGoogle ScholarPubMed
Perez-Iglesias, R, Mata, I, Amado, JA, Berja, A, Garcia-Unzueta, MT, Martínez García, O, Arranz, MJ, Vazquez-Barquero, JL and Crespo-Facorro, B (2010) Effect of FTO, SH2B1, LEP, and LEPR polymorphisms on weight gain associated with antipsychotic treatment. Journal of Clinical Psychopharmacology 30, 661–666.CrossRefGoogle ScholarPubMed
Philippe, J, Stijnen, P, Meyre, D, De Graeve, F, Thuillier, D, Delplanque, J, Gyapay, G, Sand, O, Creemers, JW, Froguel, P and Bonnefond, A (2015) A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. International Journal of Obesity 2005 39, 295–302.CrossRefGoogle ScholarPubMed
Piao, L, Park, J, Li, Y, Shin, S, Shin, S, Kong, G, Shrestha, R, Tran, Q, Hur, GM, Kim, JL and Park, J (2014) SOCS3 and SOCS6 are required for the risperidone-mediated inhibition of insulin and leptin signaling in neuroblastoma cells. International Journal of Molecular Medicine 33, 1364–1370.CrossRefGoogle ScholarPubMed
Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MAR, Bender, D, Maller, J, Sklar, P, de Bakker, PI, Daly, MJ and Sham, PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. The American Journal of Human Genetics 81, 559–575.CrossRefGoogle ScholarPubMed
R Foundation for Statistical Computing (2013) R: A language and environment for statistical computing. [Internet]. R Development Core Team. Available from: http://www.R-project.org/Google Scholar
Ramos-Molina, B, Martin, MG and Lindberg, I (2016) PCSK1 variants and human obesity. Progress in Molecular Biology and Translational Science 140, 47–74.CrossRefGoogle ScholarPubMed
Reynolds, GP, Yevtushenko, OO, Gordon, S, Arranz, B, San, L and Cooper, SJ (2013) The obesity risk gene FTO influences body mass in chronic schizophrenia but not initial antipsychotic drug-induced weight gain in first-episode patients. The International Journal of Neuropsychopharmacology 16, 1421–1425.CrossRefGoogle Scholar
Roerig, JL, Steffen, KJ and Mitchell, JE (2011) Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs 25, 1035–1059.CrossRefGoogle ScholarPubMed
Rojczyk, E, Pałasz, A and Wiaderkiewicz, R (2015) Effect of short and long-term treatment with antipsychotics on orexigenic/anorexigenic neuropeptides expression in the rat hypothalamus. Neuropeptides 51, 31–42.CrossRefGoogle Scholar
Rouillé, Y, Kantengwa, S, Irminger, JC and Halban, PA (1997) Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1. Journal of Biological Chemistry 272, 32810–32816.CrossRefGoogle ScholarPubMed
Sarzynski, MA, Jacobson, P, Rankinen, T, Carlsson, B, Sjöström, L, Bouchard, C and Carlsson, LM (2011) Associations of markers in 11 obesity candidate genes with maximal weight loss and weight regain in the SOS bariatric surgery cases. International Journal of Obesity 2005 35, 676–683.CrossRefGoogle ScholarPubMed
Scigliano, G and Ronchetti, G (2013) Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia: a novel mechanistic hypothesis. CNS Drugs 27, 249–257.CrossRefGoogle ScholarPubMed
Shams, TA and Müller, DJ (2014) Antipsychotic induced weight gain: genetics, epigenetics, and biomarkers reviewed. Current Psychiatry Reports 16, 473.CrossRefGoogle ScholarPubMed
Slattery, ML, Lundgreen, A, Hines, L, Wolff, RK, Torres-Mejia, G, Baumgartner, KN and John, EM (2015) Energy homeostasis genes and breast cancer risk: the influence of ancestry, body size, and menopausal status, the breast cancer health disparities study. Cancer Epidemiology 39, 1113–1122.CrossRefGoogle ScholarPubMed
Soeiro-de-Souza, MG, Gold, PW, Brunoni, AR, de Sousa, RT, Zanetti, MV, Carvalho, AF, Gattaz, WF, Machado-Vieira, R and Teixeira, AL (2014). Lithium decreases plasma adiponectin levels in bipolar depression. Neuroscience Letters 564, 111–114.CrossRefGoogle ScholarPubMed
Solanki, RK, Singh, P, Midha, A and Chugh, K (2008) Schizophrenia: impact on quality of life. Indian Journal of Psychiatry 50, 181–186.Google ScholarPubMed
Song, X, Pang, L, Feng, Y, Fan, X, Li, X, Zhang, W, Gao, J, Zhang, J, Nemani, K, Zhang, H and Lv, L (2014) Fat-mass and obesity-associated gene polymorphisms and weight gain after risperidone treatment in first episode schizophrenia. Behavioral and Brain Functions 10, 35.CrossRefGoogle ScholarPubMed
Stroup, TS, McEvoy, JP, Swartz, MS, Byerly, MJ, Glick, ID, Canive, JM, McGee, MF, Simpson, GM, Stevens, MC and Lieberman, JA (2003) The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophrenia Bulletin 29, 15–31.CrossRefGoogle ScholarPubMed
Tanofsky-Kraff, M, Han, JC, Anandalingam, K, Shomaker, LB, Columbo, KM, Wolkoff, LE, Kozlosky, M, Elliott, C, Ranzenhofer, LM, Roza, CA, Yanovski, SZ and Yanovski, JA (2009) The FTO gene rs9939609 obesity-risk allele and loss of control over eating. American Journal of Clinical Nutrition 90, 1483–1488.CrossRefGoogle ScholarPubMed
Templeman, LA, Reynolds, GP, Arranz, B and San, L (2005) Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenetics and Genomics 15, 195–200.CrossRefGoogle ScholarPubMed
Tiwari, AK, Zai, CC, Meltzer, HY, Lieberman, JA, Müller, DJ and Kennedy, JL (2010) Association study of polymorphisms in insulin induced gene 2 (INSIG2) with antipsychotic-induced weight gain in European and African-American schizophrenia patients. Human Psychopharmacology Clinical and Experimenta 25, 253–259.CrossRefGoogle ScholarPubMed
Tontonoz, P and Spiegelman, BM (2008) Fat and beyond: the diverse biology of PPARgamma. Annual Review of Biochemistry 77, 289–312.CrossRefGoogle ScholarPubMed
Vasudev, K, Choi, Y-H, Norman, R, Kim, RB and Schwarz, UI (2017) Genetic determinants of clozapine-induced metabolic side effects. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie 62, 138–149.CrossRefGoogle ScholarPubMed
Walley, AJ, Asher, JE and Froguel, P (2009) The genetic contribution to non-syndromic human obesity. Nature Reviews Genetics 10, 431–442.CrossRefGoogle ScholarPubMed
Wang, C-Y, Shie, S-S, Wen, M-S, Hung, K-C, Hsieh, I-C, Yeh, T-S and Wu, D (2015) Loss of FTO in adipose tissue decreases Angptl4 translation and alters triglyceride metabolism. Science Signaling 8, ra127.CrossRefGoogle ScholarPubMed
Wangensteen, T, Egeland, T, Akselsen, H, Holmen, J, Undlien, D and Retterstøl, L (2010) FTO genotype and weight gain in obese and normal weight adults from a Norwegian population based cohort (the HUNT study). Experimental and Clinical Endocrinology & Diabetes: Official Journal of German Society Endocrinology [and] German Diabetes Association 118, 649–652.CrossRefGoogle Scholar
Wasim, M, Awan, FR, Najam, SS, Khan, AR and Khan, HN (2016) Role of leptin deficiency, inefficiency, and leptin receptors in obesity. Biochemical Genetics 54, 565–572.CrossRefGoogle ScholarPubMed
Weston-Green, K, Huang, X-F and Deng, C (2012) Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain. PLoS ONE 7, e33548.CrossRefGoogle ScholarPubMed
Wu, R, Zhao, J, Shao, P, Ou, J and Chang, M (2011) Genetic predictors of antipsychotic-induced weight gain: a case-matched multi-gene study. Journal of Central South University. Medical Sciences. Zhong Nan Da Xue Xue Bao Yi Xue Ban 36, 720–723.Google ScholarPubMed
Yeo, GSH (2014) The role of the FTO (Fat Mass and Obesity Related) locus in regulating body size and composition. Molecular and Cellular Endocrinology 397, 34–41.CrossRefGoogle ScholarPubMed
Yevtushenko, OO, Cooper, SJ, O’Neill, R, Doherty, JK, Woodside, JV and Reynolds, GP (2008) Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia. British Journal of Psychiatry: The Journal of Mental Science 192, 424–428.CrossRefGoogle ScholarPubMed
Yu, G and He, Q-Y (2016) ReactomePA: an R/Bioconductor package for reactome pathway analysis and visualization. Molecular BioSystems 12, 477–479.CrossRefGoogle Scholar
Zai, CCH, Tiwari, AK, Chowdhury, NI, Brandl, EJ, Shaikh, SA, Freeman, N, Lieberman, JA, Meltzer, HY, Müller, DJ and Kennedy, JL (2015) Association study of GABAA α2 receptor subunit gene variants in antipsychotic-associated weight gain. Journal of Clinical Psychopharmacology 35, 7–12.CrossRefGoogle ScholarPubMed
Zhang, J-P, Lencz, T, Zhang, RX, Nitta, M, Maayan, L, John, M, Robinson, DG, Fleischhacker, WW, Kahn, RS, Ophoff, RA, Kane, JM, Malhotra, AK and Correll, CU (2016) Pharmacogenetic associations of antipsychotic drug-related weight gain: a systematic review and meta-analysis. Schizophrenia Bulletin 42, 1418–1437.CrossRefGoogle ScholarPubMed
Zhao, X, Yang, Y, Sun, B-F, Zhao, Y-L and Yang, Y-G (2014) FTO and obesity: mechanisms of association. Current Diabetes Reports 14, 486.CrossRefGoogle ScholarPubMed
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