Identification of the Risk Genes Associated With Vulnerability to Addiction: Major Findings From Transgenic Animals

Understanding risk factors for substance use disorders (SUD) can facilitate medication development for SUD treatment. While a rich literature exists discussing environmental factors that influence SUD, fewer articles have focused on genetic factors that convey vulnerability to drug use. Methods to identify SUD risk genes include Genome-Wide Association Studies (GWAS) and transgenic approaches. GWAS have identified hundreds of gene variants or single nucleotide polymorphisms (SNPs). However, few genes identified by GWAS have been verified by clinical or preclinical studies. In contrast, significant progress has been made in transgenic approaches to identify risk genes for SUD. In this article, we review recent progress in identifying candidate genes contributing to drug use and addiction using transgenic approaches. A central hypothesis is if a particular gene variant (e.g., resulting in reduction or deletion of a protein) is associated with increases in drug self-administration or relapse to drug seeking, this gene variant may be considered a risk factor for drug use and addiction. Accordingly, we identified several candidate genes such as those that encode dopamine D2 and D3 receptors, mGluR2, M4 muscarinic acetylcholine receptors, and α5 nicotinic acetylcholine receptors, which appear to meet the risk-gene criteria when their expression is decreased. Here, we describe the role of these receptors in drug reward and addiction, and then summarize major findings from the gene-knockout mice or rats in animal models of addiction. Lastly, we briefly discuss future research directions in identifying addiction-related risk genes and in risk gene-based medication development for the treatment of addiction.

Biventricular non-compaction cardiomyopathy and tricuspid hypoplasia in a novel non-POU domain-containing octamer-binding gene variant

A maternally inherited novel pathogenic non-POU domain-containing octamer-binding gene variant c.767G>T, p.R256I [NM_001145408], manifested in a male infant as dilated cardiomyopathy with severe left ventricular dysfunction and dilation, biventricular non-compaction, tricuspid hypoplasia, and hydrocephaly. To the best of our knowledge, no previous non-POU domain-containing octamer-binding gene variants with biventricular non-compaction have been associated with tricuspid valve hypoplasia. Hence, this case introduces a new pathogenic variant observed in the non-POU domain-containing octamer-binding gene and adds to the range of cardiac phenotypes identified in non-POU domain-containing octamer-binding gene variants.

A Case of Carbamazepine-Induced Aggravation of Self-Limited Epilepsy with Centrotemporal Spikes Epilepsy and Valproate-Induced Hyperammonemic Encephalopathy in a Child with Heterozygous Gene Variant of Carbomoyl Phosphatase Synthetase Deficiency

Antiepileptics drugs are the mainstay of the management of epilepsy in children. Sodium valproate (VPA) and carbamazepine (CBZ) are widely used medications in childhood epilepsy. Hyperammonemia has been described as a known side effect of valproate therapy. It is known that VPA-associated HA is common among patients who hold genetic mutations of the carbomoyl phosphatase synthase 1 gene (CPS1). Aggravation of self-limited epilepsy with centrotemporal spikes (SLECTS) is a rare side effect of CBZ. Here, we present a child who had CBZ-induced aggravation of rolandic epilepsy and VPA-induced HA encephalopathy in the background of an unrecognised heterozygous gene variant of CPS1. An 8-year-old boy with SLECTS presented with a history of abnormal behaviours and drowsiness. He was apparently well until six years when he developed seizures in favour of rolandic epilepsy. His electroencephalogram (EEG) showed bilateral predominantly on the right-sided central-temporal spikes and waves. The diagnosis of SLECTS was made, and he was commenced on CBZ. Though he showed some improvement at the beginning, his seizure frequency increased when the dose of CBZ was increased. His repeat EEG showed electrical status in slow-wave sleep, and CBZ was stopped. Subsequently, he was started on VPA, and with that, he developed features of encephalopathy. He had elevated serum ammonia with normal liver functions. VPA was stopped with the suspicion of VPA-induced hyperammonemia. Tandem mass spectrometry did not show significant abnormality in the amino acid profile. Specific genetic analysis revealed a c.2756 C > T.p (Ser919Leu) heterozygote genetic mutation of the CSP 1 gene. This is a classic example where side effects of treatment determine the choice of antiepileptics drugs (AEDs) in childhood epilepsy. It is essential to keep in mind that SLECTS can be aggravated with certain AEDs, and VPA-induced HA in the absence of live failure could be due to underlying inherited metabolic disorders.

The CYP24A1 Gene Variant rs2762943 Is Associated With Low Serum 1,25- Dihydroxyvitamin D Levels In Multiple Sclerosis Patients

Background: Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. We recently identified a polymorphism located in the cytochrome P450 family 24 subfamily A member 1 (CYP24A1) gene, rs2762943, that was found to be associated with an increased risk for MS. CYP24A1 codes for a protein that is involved in the catabolism of the active form of vitamin D. Here, we investigated the immunological effects of carrying the risk allele for the rs2762943 polymorphism, as well as its role as genetic modifier in MS patients. Methods: Serum levels of 25‐hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in a cohort of 167 MS patients. In a subgroup of these patients, expression levels of MHC class II and co-stimulatory molecules were determined by flow cytometry in blood cell populations, and the levels of proinflammatory (IFNG, GM-CSF, CXCL13) and anti-inflammatory (IL-10) cytokines and neurofilament light chain were measured by single-molecule array assays in serum samples. The effect of the rs2762943 polymorphism on disease activity and disability progression measures was evaluated in a cohort of 340 MS patients. Results: Compared to non-carriers, MS patients carrying the risk allele for rs2762943 were characterized by reduced levels of 1,25(OH)2D (p=0.0001), and elevated levels of IFNG (p=0.03) and GM-CSF (p=0.008), whereas no significant differences were observed between risk allele carriers and non-carriers groups for the other evaluated markers. The presence of the risk allele for rs2762943 had no significant impact on the annualized relapse rate, EDSS and MSSS measures during follow-up. However, risk allele carriers were younger at disease onset (p=0.04). Discussion: These findings suggest that the CYP24A1 rs2762943 gene variant plays a more important role on MS susceptibility than on disease prognosis, and is associated with lower 1,25(OH)2D levels and heightened pro-inflammatory environment in MS patients.