A comprehensive analysis of mitochondrial genes variants and their association with antipsychotic-induced weight gain

Abstract

Antipsychotic Induced Weight Gain (AIWG) is a common and severe side effect of many antipsychotic medications. Mitochondria play a vital role for whole-body energy homeostasis and there is increasing evidence that antipsychotics modulate mitochondrial function. This study aimed to examine the role of variants in nuclear-encoded mitochondrial genes and the mitochondrial DNA (mtDNA) in conferring risk for AIWG. We selected 168 European-Caucasian individuals from the CATIE sample based upon meeting criteria of multiple weight measures while taking selected antipsychotics (risperidone, quetiapine or olanzapine). We tested the association of 670 nuclear-encoded mitochondrial genes with weight change (%) using MAGMA software. Thirty of these genes showed nominally significant P-values (< 0.05). We were able to replicate the association of three genes, CLPB, PARL, and ACAD10, with weight change (%) in an independent prospectively assessed AIWG sample. We analyzed mtDNA variants in a subset of 74 of these individuals using next-generation sequencing. No common or rare mtDNA variants were found to be significantly associated with weight change (%) in our sample. Additionally, analysis of mitochondrial haplogroups showed no association with weight change (%). In conclusion, our findings suggest nuclear-encoded mitochondrial genes play a role in AIWG. Replication in larger sample is required to validate our initial report of mtDNA variants in AIWG.

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.