A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses

Abstract

Antipsychotics can induce in schizophrenic (SZ) and bipolar disorder (BP) patients serious body weight changes that increase risk for noncompliance to medication, and risk for cardiovascular diseases and diabetes. A genetic origin for this susceptibility to weight changes has been hypothesized because only a proportion of treated patients are affected, the degree of affection differing also in rates and magnitudes. In a first genome scan on obesity under antipsychotics in SZ and BP, we analyzed 21 multigenerational kindreds (508 family members) including several patients treated for a minimum of 3 years mainly with haloperidol or chlopromazine. Obesity was defined from medical files and was shown to be 2.5 times more frequent in patients treated with antipsychotics than in untreated family members (30 vs 12%). The nine pedigrees that showed at least two occurrences of obesity under antipsychotics were submitted to model-based linkage analyses. We observed a suggestive linkage with a multipoint Lod score (MLS) of 2.74 at 12q24. This linkage finding vanished when we used as phenotypes, obesity unrelated to antipsychotics, and when we used SZ or BP. This suggests that this positive linkage result with obesity is specific to the use of antipsychotics. A potential candidate gene for this linkage is the pro-melanin-concentrating hormone (PMCH) gene located at less then 1 cM of the linkage. PMCH encodes a neuropeptide involved in the control of food intake, energy expenditure, and in anxiety/depression. This first genome scan targeting the obesity side effect of antipsychotics identified 12q24 as a susceptibility region. Keywords: schizophrenia; bipolar disorder; melanin-concentrating hormone Adverse metabolic effects of antipsychotics such as weight gain may contribute to noncompliance with treatment and may lead to medical morbidity when obesity is reached.1 Indeed, obesity, as defined by a body mass index (BMI) of 30 kg/m 2 and greater 2 is associated with higher risks of developing cardiovascular diseases, hypertension, type II diabetes, dyslipidemia, arthritis, and some forms of cancer. The estimate of the proportion of schizophrenic (SZ)-or bipolar disorder (BP)-treated patients experiencing significant weight gain for a given antipsychotic varies between 10 and 50%, according to the population studied, and the dose and the duration of the follow-up. For example, 25% of the patients treated with fluphenazine experienced significant weight gain after 1 month, and this proportion reaches 50% in 1 year.3 In patients treated with olanzapine for up to 3 years, weight gain tended toward a plateau at approximately 36 weeks. 4 The proportion of patients experiencing weight gain also varies according to the antipsychotic used, the greatest proportion being observed with olanzapine and clozapine, followed by chlorpromazine and thioridazine/ mesoridazine, and the lowest with ziprasidone and molindone, the latter even inducing a weight loss. 5Antipsychotics can also induce other metabolic perturbations such as hyperglycemia,...

Metabolic syndrome and related variables, insulin resistance, leptin levels, and PPAR-γ2 and leptin gene polymorphisms in a pedigree of subjects with bipolar disorder

“…In fact, a large study of a multigenerational kindred (508 relatives) including members with BD or schizophrenia in Quebec, Canada, showed obesity to be 2.5 times more frequent in antipsychotictreated patients (30%) than in untreated family members (12%). 13 This finding suggests that medication plays a role in the development of obesity. By contrast, in a large epidemiological study comprising data from the general population (GP), the authors reported that drug-free BD relatives showed the highest frequency of MS, obesity, and abnormal glucose and diastolic blood pressure (BP) levels among several comparison groups, including drugtreated patients and their relatives.…”

Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort

“…8,25 In another study, linkage for obesity was also found to 12q24 in patients on antipsychotic medication. 40 Recently, Li et al 41 have shown significant linkage for obesity-related traits: percentage fat (LOD 3.79; P ¼ 0.00001), BMI (LOD 2.98; P ¼ 0.0001) and waist circumference (LOD 2.86; P ¼ 0.00014) to chromosome 12q23 -24. Their fine-mapping data localized linkages for those traits to 116 -125 cM on chromosome 12.…”

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

“…276 Additionally, a genomewide linkage study of obesity in patients undergoing treatment with classical antipsychotics identified suggestive linkage (MLS = 2.74) at 12q24. 297 The gene coding for pro-melanin-concentrating hormone, involved in the control of food intake and energy regulation, is located near this region and is a potential candidate gene for drug-induced weight gain. A recent study found differences in genetic patterns associated with weight gain in olanzapine and risperidone treatment.…”

“…This approach has already been successfully used for the identification of genes related to warfarin dose-response levels 315 and to drug-induced weight gain. 297 Nevertheless, this strategy still requires genotyping of large number of variants in clinical samples of moderate-large size. Genotyping techniques have been adapted to these new necessities and a wide range of high-throughput methodologies are available.…”