Analysis of single-cell transcriptome data from a mouse model implicates protein synthesis dysfunction in schizophrenia.

Background: Schizophrenia is a mental disorder that causes considerable morbidity, whose risk largely results from genetic factors. Setd1a is a gene implicated in schizophrenia.

Objective: To study the gene expression changes found in heterozygous Setd1a knockout mice in order to gain useful insight into schizophrenia pathogenesis.

Single Nucleus Transcriptome Data from Alzheimer's Disease Mouse Models Yield New Insight into Pathophysiology.

Background: 5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer's disease (AD)-related pathology.

Objective: To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice.

Methods: Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models.

Inherited L1 Retrotransposon Insertions Associated With Risk for Schizophrenia and Bipolar Disorder.

Studies of the genetic heritability of schizophrenia and bipolar disorder examining single nucleotide polymorphisms (SNPs) and copy number variations have failed to explain a large portion of the genetic liability, resulting in substantial missing heritability. Long interspersed element 1 (L1) retrotransposons are a type of inherited polymorphic variant that may be associated with risk for schizophrenia and bipolar disorder. We performed REBELseq, a genome wide assay for L1 sequences, on DNA from male and female persons with schizophrenia and controls ( = 63 each) to identify inherited L1 insertions and validated priority insertions.

Analysis of differential gene expression and transcript usage in hippocampus of Apoe null mutant mice: Implications for Alzheimer's disease.

A dataset of single-nucleus RNA sequencing (snRNAseq) data was analyzed using Seurat, Sierra, and Ingenuity Pathway Analysis (IPA) programs to assess differentially expressed genes (DEGs) and differential transcript usage (DTU) in mouse hippocampal cell types. Seurat identified DEGs between the wild type (WT) and Apoe knockout (EKO) mice. IPA identified 11 statistically significant canonical pathways in >1 cell type.

Neonatal Opioid Withdrawal Syndrome (NOWS): A Transgenerational Echo of the Opioid Crisis.

The incidence of neonatal opioid withdrawal syndrome (NOWS) has increased substantially in the setting of the opioid epidemic, a major public health problem in the United States. At present, NOWS has commonly used assessment and treatment protocols, but new protocols have questioned old practices. However, because of limited access to opioid use disorder (OUD) treatment and socioeconomic factors, many pregnant (and postpartum) women with OUD do not receive treatment.

Restriction Enzyme Based Enriched L1Hs Sequencing (REBELseq): A Scalable Technique for Detection of Ta Subfamily L1Hs in the Human Genome.

Long interspersed element-1 retrotransposons (LINE-1 or L1) are ∼6 kb mobile DNA elements implicated in the origins of many Mendelian and complex diseases. The actively retrotransposing L1s are mostly limited to the L1 human specific (L1Hs) transcriptional active (Ta) subfamily. In this manuscript, we present REBELseq as a method for the construction of Ta subfamily L1Hs-enriched next-generation sequencing libraries and bioinformatic identification.

Association analysis between polymorphisms in the myo-inositol monophosphatase 2 (IMPA2) gene and bipolar disorder.

Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The myo-inositol monophosphatase 2 gene (IMPA2) maps to this genomic region. Myo-inositol monophosphatase dephosphorylates inositol monophosphate, regenerating free inositol.

Association between polymorphisms in the metallophosphoesterase (MPPE1) gene and bipolar disorder.

Genetic linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The metallophosphoesterase (MPPE1) gene maps to this region. Dysregulation of protein phosphorylation and subsequent abnormal cellular signaling has been postulated to be involved in neuropsychiatric disorders thus making MPPE1 a plausible biological candidate gene for BPD.

Association between the catechol-O-methyltransferase Val158Met polymorphism and cocaine dependence.

Dopaminergic brain systems have been documented to have a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The catechol-O-methyltransferase (COMT) is involved in the degradation of catecholamines and a functional polymorphism (Val158Met) has been suggested to influence enzyme activity. In this study we hypothesize that genetic variation in the COMT gene contributes to increased risk for cocaine dependence.

Association between polymorphisms in the vesicle-associated membrane protein-associated protein A (VAPA) gene on chromosome 18p and bipolar disorder.

Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The vesicle-associated membrane protein-associated protein A (VAPA) gene maps to this region. VAPA interacts with presynaptic proteins and is necessary for vesicular neurotransmission.

Genetic variants in the cocaine- and amphetamine-regulated transcript gene (CARTPT) and cocaine dependence.

Dopaminergic brain systems have been implicated to play a major role in drug reward, thus making genes involved in these circuits plausible candidates for susceptibility to substance use disorders. The cocaine- and amphetamine-regulated transcript peptide (CARTPT) is involved in reward and feeding behavior and has functional characteristics of an endogenous psychostimulant. In this study we tested the hypothesis that variation in the CARTPT gene increases susceptibility to cocaine dependence in individuals of African descent.

Association between polymorphisms in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) on chromosome 8p and schizophrenia.

Linkage studies have suggested a susceptibility locus for schizophrenia (SZ) exists on chromosome 8p21-22. The vesicular monoamine transporter 1 gene (VMAT1), also known as SLC18A1, maps to this SZ susceptibility locus. Vesicular monoamine transporters are involved in the presynaptic vesicular packaging of monoamine neurotransmitters, which have been postulated to play a role in the etiology of SZ.

Association analysis of the pituitary adenylate cyclase-activating polypeptide (PACAP/ADCYAP1) gene in bipolar disorder.

Background: Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The pituitary adenylate cyclase-activating polypeptide/adenylate cyclase-activating polypeptide 1 (pituitary) (PACAP/ADCYAP1) gene maps to this region. PACAP is a neuropeptide involved in neurotransmission in both the peripheral nervous system and central nervous system and is required for catecholamine secretion.

No association between polymorphisms in the prostate apoptosis factor-4 gene and cocaine dependence.

Objective: A number of studies have investigated the genes underlying dopamine, serotonin, and glutamine neurotransmitter systems in order to find a genetic basis for the pathology of cocaine dependence. The gene that encodes the prostate apoptosis factor-4 (Par-4) protein is located in the 12q21 region and has been shown to directly interact with the D2 dopamine receptor and through such interaction is thought to directly affect the activity of D2 receptors. The aim of this study is to investigate whether polymorphisms in the human Par-4 gene contribute to the etiology of cocaine dependence.

Analysis of variations in the tryptophan hydroxylase-2 (TPH2) gene in cocaine dependence.

While the exact physiological mechanisms underlying cocaine dependence remain unclear, a growing body of evidence indicates a role for the serotonergic neurotransmitter system in the pathology of this substance use disorder. The focus of the present study is to determine whether genetic variation in the tryptophan hydroxylase-2 (TPH2) gene, which encodes the enzyme responsible for synthesis of the majority of the serotonin contained in neurons of the central nervous system, contributes to the pathophysiology of cocaine dependence. To examine this hypothesis, we used a case-control study design in which the genotype and allele distributions for six single nucleotide polymorphisms (SNPs) in the TPH2 gene were compared between cocaine-dependent (n = 299) and control individuals (n = 208) of African descent.

Analysis of variations in the NAPG gene on chromosome 18p11 in bipolar disorder.

Objective: A number of studies have implicated the chromosome 18p11 region as a susceptibility region for bipolar disorder. The gene encoding gamma-SNAP (NAPG), one of three soluble N-ethylmaleimide-sensitive fusion (NSF)-attachment proteins (SNAPs), is located in the 18p11 region and is thought to play a role in cellular processes required for neurotransmission in the central nervous system. The purpose of this study is to investigate whether polymorphisms in the human NAPG gene contribute to the etiology of bipolar disorder.

Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population.

Objective: While twin and adoption studies have demonstrated that up to 70% of the risk for becoming addicted to cocaine is due to genetic factors, identifying specific genes involved in the development or progression of cocaine dependence has been difficult. The purpose of this study is to determine whether single-nucleotide polymorphisms in the Homer1 and Homer2 genes associate with the cocaine-dependent phenotype in an African American population.

Methods: This study utilized a case-control design in which the genotype and allele frequencies for four single-nucleotide polymorphisms in the Homer1 gene and three single-nucleotide polymorphisms in the Homer2 gene were compared between African American individuals with a diagnosis of cocaine dependence (n=170) and African American individuals with no history of substance abuse (n=90).

Confirmation of the association between a polymorphism in the promoter region of the prodynorphin gene and cocaine dependence.

The endogenous opioid system has been shown to have a role in the biological processes involved in addiction to numerous drugs of abuse including cocaine. It has recently been reported that the variable nucleotide tandem repeat (VNTR) polymorphism in the 5' promoter region of the prodynorphin gene, which encodes the precursor for three endogenous opioid peptides, is associated with the cocaine dependent phenotype. In order to confirm this finding, we genotyped the prodynorphin promoter polymorphism in cocaine dependent (n = 167) and control (n = 88) individuals of African descent.