Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample

Abstract

Observations of impaired glucose regulation in schizophrenia are long-standing, although their pathological and etiological significance is uncertain. One approach to the issue that minimizes environmental variables (e.g., medication and diet) is to determine whether genes related to glucose regulation show genetic linkage to schizophrenia. We examined the potential role of glucose metabolism in schizophrenia through a genome scan of affection status in schizophrenia and an empirical method for deriving P-values. Data were utilized from the NIMH Genetics Initiative for Schizophrenia dataset, which comprises a total sample consisting of 71 pedigrees containing 218 nuclear families and 987 individuals. A genome scan with 459 markers spaced at an average of 10 cM intervals was conducted using the linkage analysis program Genehunter separately for European- and African-American groups. Enzymes that regulate glycolysis were identified and the genes regulating these enzymes were located through the Online Mendelian Inheritance in Man (OMIM) website. The focus in this study was on genes located near previously reported schizophrenia susceptibility regions. The genome-wide significance of these genes to schizophrenia was assessed using permutation testing. When results were adjusted for multiple testing within and across ethnic groups, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2; chromosome 1q32.2) achieved genome-wide significance (P = 0.04). In addition, hexokinase 3 (HK3; chromosome 5q35.3) was also suggestive of linkage (P = 0.09). For the European-American sample, PFKFB2 (1q32.2), hexokinase 3 (HK3; 5q35.3), and pyruvate kinase 3 (PK3; chromosome 15q23) achieved significance at the 0.05 level. None of the genes showed significance in the African-American sample. Our results provide further support for the view that genes that regulate glucose metabolism may also influence susceptibility to schizophrenia. More generally, they support the view that relationships between glucose dysregulation and schizophrenia are inherent to the disorder, and are not merely epiphenomena related to medication or other treatment factors.

Chronic Olanzapine Treatment Causes Differential Expression of Genes in Frontal Cortex of Rats as Revealed by DNA Microarray Technique

“…Stone et al (2004) identified positive associations between schizophrenia and several enzymes involved in glycolysis, including 6-phosphofructo-2-kinase/fructose-2, 6-biphophatase 2, hexokinase 3, and pyruvate kinase 3. Similarly, olanzapine treatment of rats caused significant alterations in several key glycolytic enzymes, such as increases in muscle glycogen phosphorylase and in RBC and liver pyruvate kinase (which also showed a near significant increase based on our QPCR results; Table 2) and a decrease in sucrase-isomaltase (Tables 1, 3).…”

“…Impairment of glycolytic pathways has been investigated in schizophrenia (Stone et al, 2004). Stone et al (2004) identified positive associations between schizophrenia and several enzymes involved in glycolysis, including 6-phosphofructo-2-kinase/fructose-2, 6-biphophatase 2, hexokinase 3, and pyruvate kinase 3.…”

“…Olanzapine upregulates pyruvate kinase, an enzyme that catalyzes the formation of pyruvate and ATP from phosphoenolpyruvate and ADP. Pyruvate kinase polymorphisms have been discovered in subjects with schizophrenia (Stone et al, 2004) and Type II diabetes (Wang et al, 2002), and olanzapine increases the risk for diabetes in subjects with schizophrenia (Meyer and Nasrallah, 2003). Olanzapine also upregulates glycogen phosphorylase, a key enzyme in glycogen degradation, leading to removal of a terminal glucose residue from the nonreducing end of a glycogen chain providing more glucose for local brain energy expenditure.…”

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

“…These changes were not attributable to antipsychotic treatment, which may have a restorative effect (11). Further, a genetic study demonstrated evidence for linkage between enzymes that control glycolysis, such as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), hexokinase 3 (HXK3), and pyruvate kinase 3 (PK3),suggesting that genetic risk for this illness includes bioenergetic substrates (14). …”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…The basic mechanisms behind these metabolic irregularities have not been fully elucidated, but it appears that antipsychotic medications could play an important role (Newcomer, 2005). Moreover, high rates of obesity and type II diabetes mellitus, observed in drug-naive/free patients (Mukherjee et al, 1996;Allison et al, 1999a;Thakore et al, 2002;Ryan et al, 2003Ryan et al, , 2004 before Kohen, 2004) and after the advent of antipsychotics and in nonschizophrenic blood relatives (Dynes, 1969;Mukherjee et al, 1989;Cheta et al, 1990;Martins et al, 2001;Lamberti et al, 2004), were potentially attributed to genetic factors (Stone et al, 2004), illness neurobiology (Thakore, 2005) and to unhealthy lifestyle (Brown et al, 1999). The interpretability of the preneuroleptic era data (reviewed in Kohen, 2004) is, however, limited by flaws in epidemiological methodology including lack of evaluation of and adjustments for adiposity, lifestyle, and anthropometric measures together with inconsistent diagnostic criteria for schizophrenia and glucose/insulin abnormalities Newcomer, 2005).…”