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

Corfitsen, Henrik Thyge; Krantz, Betina; Drago, Antonio

doi:10.1017/neu.2019.41

Cited by 15 publications

(11 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetic associations between pathogenic genes and genes involved in lipid metabolism cannot be ruled out as feasible links in body weight changes in response to psychotropic treatments. In fact, lipoprotein lipase (LPL), a key enzyme in triglyceride hydrolysis, is expressed in brain regions which are structural substrates of higher activities of the CNS (learning, memory, behavior, cognition), and SNPs in the LPL gene locus (8p22) (rs253 C allele) have been associated with SCZ [208].…”

Section: Mechanismmentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

View full text Add to dashboard Cite

Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

show abstract

Section: Mechanismmentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Two studies utilized data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (225), both failing to detect genome-wide significant signals. The first also reported trends in SNPs upstream of opioid growth factor receptor OGFRL1 (226), and the second highlighted enrichment of nominally associated SNPs in energy balance pathway genes by hypothesis-driven pathway enrichment analysis (227). A SNP (rs10977144) located in the protein tyrosine phosphatase, receptor type D gene (PTPRD) (228) was associated with AIWG in a GWAS of Chinese patients with schizophrenia (n = 524, mean age = 26.4).…”

Section: Genetic Predispositionmentioning

confidence: 99%

The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children

Libowitz

Nurmi

2021

Front. Psychiatry

View full text Add to dashboard Cite

Antipsychotic medications are critical to child and adolescent psychiatry, from the stabilization of psychotic disorders like schizophrenia, bipolar disorder, and psychotic depression to behavioral treatment of autism spectrum disorder, tic disorders, and pediatric aggression. While effective, these medications carry serious risk of adverse events—most commonly, weight gain and cardiometabolic abnormalities. Negative metabolic consequences affect up to 60% of patients and present a major obstacle to long-term treatment. Since antipsychotics are often chronically prescribed beginning in childhood, cardiometabolic risk accumulates. An increased susceptibility to antipsychotic-induced weight gain (AIWG) has been repeatedly documented in children, particularly rapid weight gain. Associated cardiometabolic abnormalities include central obesity, insulin resistance, dyslipidemia, and systemic inflammation. Lifestyle interventions and medications such as metformin have been proposed to reduce risk but remain limited in efficacy. Furthermore, antipsychotic medications touted to be weight-neutral in adults can cause substantial weight gain in children. A better understanding of the biological underpinnings of AIWG could inform targeted and potentially more fruitful treatments; however, little is known about the underlying mechanism. As yet, modest genetic studies have nominated a few risk genes that explain only a small percentage of the risk. Recent investigations have begun to explore novel potential mechanisms of AIWG, including a role for gut microbiota and microbial metabolites. This article reviews the problem of AIWG and AP metabolic side effects in pediatric populations, proposed mechanisms underlying this serious side effect, and strategies to mitigate adverse impact. We suggest future directions for research efforts that may advance the field and lead to improved clinical interventions.

show abstract

“…As a result, this category included a total of 6 GWAS-reported loci (MAP2K3, MAP2K5, MET, PPARG, PROX1, and SIRT1). Among them, it highlights (MAP2K5 and PPARG) with a negative effect on the endothelial cell migration, for which SNPs have been repeatedly associated with obesity in several populations (especially in Asians) [63,91,[99][100][101][102][103][104]106,107]. The rest of these loci were involved in a positive regulation of the endothelial cell migration, and their SNPs have been associated not only with an increased risk of obesity but also with T2D or gestational diabetes mellitus [97,98,105,[108][109][110].…”

Section: Whole-genome Genetic Approaches Reveal the Implication Of Ecmentioning

confidence: 99%

Omics Approaches in Adipose Tissue and Skeletal Muscle Addressing the Role of Extracellular Matrix in Obesity and Metabolic Dysfunction

Anguita‐Ruiz

Bustos-Aibar

Plaza‐Díaz

et al. 2021

IJMS

View full text Add to dashboard Cite

Extracellular matrix (ECM) remodeling plays important roles in both white adipose tissue (WAT) and the skeletal muscle (SM) metabolism. Excessive adipocyte hypertrophy causes fibrosis, inflammation, and metabolic dysfunction in adipose tissue, as well as impaired adipogenesis. Similarly, disturbed ECM remodeling in SM has metabolic consequences such as decreased insulin sensitivity. Most of described ECM molecular alterations have been associated with DNA sequence variation, alterations in gene expression patterns, and epigenetic modifications. Among others, the most important epigenetic mechanism by which cells are able to modulate their gene expression is DNA methylation. Epigenome-Wide Association Studies (EWAS) have become a powerful approach to identify DNA methylation variation associated with biological traits in humans. Likewise, Genome-Wide Association Studies (GWAS) and gene expression microarrays have allowed the study of whole-genome genetics and transcriptomics patterns in obesity and metabolic diseases. The aim of this review is to explore the molecular basis of ECM in WAT and SM remodeling in obesity and the consequences of metabolic complications. For that purpose, we reviewed scientific literature including all omics approaches reporting genetic, epigenetic, and transcriptomic (GWAS, EWAS, and RNA-seq or cDNA arrays) ECM-related alterations in WAT and SM as associated with metabolic dysfunction and obesity.

show abstract

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

Cited by 15 publications

References 108 publications

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children

Omics Approaches in Adipose Tissue and Skeletal Muscle Addressing the Role of Extracellular Matrix in Obesity and Metabolic Dysfunction

Contact Info

Product

Resources

About