A comprehensive analysis of mitochondrial genes variants and their association with antipsychotic-induced weight gain
Introduction
Schizophrenia (SCZ) is a complex disorder characterized by psychosis and disturbed behavior. It is estimated to affect approximately 1% of the adult population worldwide (McGuffin et al., 1995). SCZ is ranked among the top 10 causes of disability among people in developed countries (Kahn et al., 2015). Antipsychotic medications are an important, effective therapeutic intervention for controlling the major symptoms of SCZ (Allison et al., 1999). However, weight gain is a common side effect of treatment with antipsychotics, and is particularly pronounced with clozapine and olanzapine, and is becoming a major health concern (Gebhardt et al., 2010). Antipsychotic-induced weight gain (AIWG) is a severe side effect observed in up to 40% of patients taking medications referred to as second-generation or atypical antipsychotics (Lett et al., 2012, Ucok and Gaebel, 2008). Weight gain leads to increased risk for cardiovascular morbidity and mortality. In addition, excessive weight and obesity can have important effects on an individual's' adjustment in the community, ability to participate in rehabilitation efforts and self-image, contributing to a main reason for non-adherence (Ucok and Gaebel, 2008). The heritability of AIWG has been suggested to be between 60 and 80% based on twin and family studies, indicating the role of genetic factors in the pathophysiology of AIWG (Gebhardt et al., 2010). Several studies have addressed the genetic basis of AIWG in terms of the nuclear genome, and it is a well-established area of research (MacNeil and Muller, 2016, Muller et al., 2013, Muller and Kennedy, 2006).
The mitochondrial system is an interesting target to be examined in AIWG studies. First, mitochondria are the main source of aerobic energy for brain cellular functioning. Second, these organelles have been shown to be involved in appetite and satiety regulation through hypothalamic signaling mechanisms. Briefly, the arcuate nucleus in the hypothalamus is the main central regulator for energy metabolism. In this region, there are two specific types of neurons: anorectic (POMC) and orexigenic (NPY/AgRP). When glucose levels are high in the cell, POMC neurons are active and promote satiety in association with elevated production of the mitochondrial reactive oxygen species (mtROS), and increased mitochondrial fusion. When glucose levels are low, NPY-AgRP neurons are active and promote hunger associated with fatty acid metabolism, low levels of mtROS, and increased mitochondria fission (Jordan et al., 2010, Nasrallah and Horvath, 2014). Finally, antipsychotic medications are reported to alter mitochondrial function although the molecular mechanisms are incompletely understood (see (Goncalves et al., 2014) for a review). Despite the rationale for mitochondrial involvement, there are not many studies examining mitochondrial genetic variance in AIWG. In one such study, our group reported the association between the NDUFS1 mitochondrial gene with AIWG (Goncalves et al., 2014). This study was the first to highlight the role of mitochondrial variation in AIWG and it prompted further, more thorough investigation of our hypothesis.
The mtDNA is a circular molecule containing 16,569 base pairs that encodes 37 genes: 13 subunits of the mitochondrial electron transport chain and a distinct set of rRNAs and tRNAs, all of which are critical for life-sustaining oxidative phosphorylation and energy generation (Wallace, 1994). Additionally, more than 1000 nuclear-encoded mitochondrial genes are necessary for mitochondrial functioning and biogenesis (Wallace, 2013). Here we hypothesize that nuclear-encoded mitochondrial genes are enriched in variants associated with AIWG. We also hypothesize that variants in the mtDNA are associated with AIWG.
Section snippets
CATIE GWAS imputation
The genome-wide genotyping in the CATIE samples was performed using Affymetrix 500 k/Perlegen's custom 164 K chips. A total of 495,172 SNPs were available. We performed standard quality control (QC) measures in CATIE sample before imputation (Anderson et al., 2010, Clarke et al., 2011). Briefly, we removed individuals with < 95% of the markers genotyped, and markers that were < 95% genotyped. We checked cryptic relatedness, and one individual of each pair of related individuals was removed (PI^ HAT >
Analysis of nuclear-encoded mitochondria gene set
Nuclear-encoded mitochondrial genes were investigated for enrichment across variants associated with weight change (%). MAGMA annotated SNPs in 11,980 genes present in our CATIE imputed data (this included 670 mitochondrial genes). In the gene-based analysis (which tests the association of each gene with the phenotype), we identified 30 mitochondrial genes with P-value < 0.05, although these observations did not survive multiple-testing correction (Table 2). We performed the gene-based analysis
Discussion
In this study, we examined the hypothesis that nuclear-encoded mitochondrial genes are associated with AIWG. The gene-set analysis did not show enrichment of mitochondrial variants to be associated with weight change (%). However, the analysis of genes individually revealed 30 nominally significant for the phenotype, of which three were replicated in an independent sample.
The most interesting finding was with the gene CLPB, which is a member of the ATP-ases (AAA +) superfamily. It cooperates
Contributors
V.F.G. designed the study, performed experiments, data analysis, and wrote the manuscript. K.M. performed data analysis and wrote first draft of manuscript. H.R. performed bioinformatics analysis. A.B.C., A.K.T., and C.C.Z. performed data analysis. A.K.T, M.M., D.J.M. performed data curation. B.R. performed libraries for sequencing. M.P.V. supervised mtDNA sequencing and performed data cleaning and quality control. J.L.K. supervised the study. All co-authors contributed with writing review &
Role of funding source
The work presented in this manuscript was supported by AFP Innovation Fund. MPV work on mitochondria and psychiatric disorders is supported by NIMH (R21MH099440-01 and R01MH085801). MPV also receives support from the Pritzker Neuropsychiatric Disorders Research Consortium. DJM is supported by the Canadian Institutes of Health Research (CIHR Operating Grant MOP 142192), the National Institutes of Health (R01MH085801), and the Centre for Addiction and Mental Health Foundation (Joanne Murphy
Disclosures
JLK, DJM, CCZ, AKT, and VFG: patent application: “Compositions and Methods for the Treatment and Prevention of Antipsychotic Medication–Induced Weight Gain”. JLK, DJM, CCZ: patent application: “Genetic Markers for Antipsychotic Induced Weight Gain and Methods for Use Thereof”. DJM is supported by the Canadian Institutes of Health Research (CIHR Operating Grant MOP 142192), the National Institutes of Health (R01MH085801), and the Centre for Addiction and Mental Health Foundation (Joanne Murphy
Acknowledgments
We are greatly indebted to the participating subjects. This work was funded by AFP Innovation Fund.
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2019, European Journal of PharmacologyCitation Excerpt :Antipsychotic-induced weight gain (AIWG) and metabolic alterations lead to cardiovascular complications, socio-occupational inabilities, decreased life expectancy and poor patient compliances. Weight gain and MetS are observed as a severe side effect observed in > 40% of patients receiving AAPs (Lett et al., 2011; Mittal et al., 2017). Patients with the first episode of psychosis (FEP) are more susceptible to getting obese as compared to those who had previous exposure to AAPs (Almandil et al., 2013).
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These authors contributed equally for this work.