Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder.

Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips.

A linkage and exome study of multiplex families with bipolar disorder implicates rare coding variants of ANK3 and additional rare alleles at 10q11-q21.

Background: Bipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness.

Methods: Overall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder-manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing.

Cortical mediation of relationships between dopamine receptor D2 and cognition is absent in youth at risk of bipolar disorder.

Bipolar disorder is associated with cognitive deficits and cortical changes for which the developmental dynamics are not well understood. The dopamine D2 receptor (DRD2) gene has been associated with both psychiatric disorders and cognitive variability. Here we examined the mediating role of brain structure in the relationship between DRD2 genomic variation and cognitive performance, with target cortical regions selected based on evidence of association with DRD2, bipolar disorder and/or cognition from prior literature.

Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders.

The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was first implicated in the cortical dysplasia-focal epilepsy (CDFE) syndrome, a recessive disease characterized by intellectual disability, epilepsy, language impairments and autistic features. Associated SNPs and heterozygous deletions in CNTNAP2 were subsequently reported in autism, schizophrenia and other psychiatric or neurological disorders.

An examination of multiple classes of rare variants in extended families with bipolar disorder.

Bipolar disorder (BD) is a complex psychiatric condition with high heritability, the genetic architecture of which likely comprises both common variants of small effect and rare variants of higher penetrance, the latter of which are largely unknown. Extended families with high density of illness provide an opportunity to map novel risk genes or consolidate evidence for existing candidates, by identifying genes carrying pathogenic rare variants. We performed whole-exome sequencing (WES) in 15 BD families (117 subjects, of whom 72 were affected), augmented with copy number variant (CNV) microarray data, to examine contributions of multiple classes of rare genetic variants within a familial context.

Vulnerability of white matter tracts and cognition to the SOD2 polymorphism: A preliminary study of antioxidant defense genes in brain aging.

Oxidative stress is a key mechanism of the aging process that can cause damage to brain white matter and cognitive functions. Polymorphisms in the superoxide dismutase 2 (SOD2) and catalase (CAT) genes have been associated with abnormalities in antioxidant enzyme activity in the aging brain, suggesting a risk for enhanced oxidative damage to white matter and cognition among older individuals with these genetic variants. The present study compared differences in white matter microstructure and cognition among 96 older adults with and without genetic risk factors of SOD2 (rs4880) and CAT (rs1001179).

BDNF Genotype Interacts with Motor Function to Influence Rehabilitation Responsiveness Poststroke.

Background: Persistent motor impairment is common but highly heterogeneous poststroke. Genetic polymorphisms, including those identified on the brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) genes, may contribute to this variability by limiting the capacity for use-dependent neuroplasticity, and hence rehabilitation responsiveness.

Objective: To determine whether BDNF and APOE genotypes influence motor improvement facilitated by poststroke upper-limb rehabilitation.

Neuromarkers of the common angiotensinogen polymorphism in healthy older adults: A comprehensive assessment of white matter integrity and cognition.

The common angiotensinogen (AGT) M268T polymorphism (rs699; historically referred to as M235T) has been identified as a significant risk factor for cerebrovascular pathologies, yet it is unclear if healthy older adults carrying the threonine amino acid variant have a greater risk for white matter damage in specific fiber tracts. Further, the impact of the threonine variant on cognitive function remains unknown. The present study utilized multiple indices of diffusion tensor imaging (DTI) and neuropsychological assessment to examine the integrity of specific white matter tracts and cognition between individuals with homozygous genotypes of M268T (MetMet n=27, ThrThr n=27).

Genetic markers of cholesterol transport and gray matter diffusion: a preliminary study of the CETP I405V polymorphism.

Variations of the cholesteryl ester transfer protein polymorphism (CETP I405V/rs5882) have been associated with an increased risk for neurodegeneration, particularly when examined in conjunction with the epsilon 4 isoform of apolipoprotein E (ApoE4). Despite these identified relationships, the impact of I405V on gray matter microstructure remains unknown. The present study examined the impact of the CETP I405V polymorphism on gray matter integrity among 52 healthy adults between ages 51 and 85.

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults.

Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population.

Triallelic relationships between the serotonin transporter polymorphism and cognition among healthy older adults.

The biallelic serotonin transporter polymorphism (5-hydroxytryptamine transporter linked polymorphic region (5-HTTLPR)) is a common genetic sequence associated with serotonin transporter (5-hydroxytryptamine transporter (5-HTT)) expression, which is further modulated by a triallelic single-nucleotide polymorphism (rs25531). Recent studies using the biallelic 5-HTTLPR have identified a beneficial role of low 5-HTT expression on cognitive performance, although no studies have examined the impact of the triallelic 5-HTTLPR/rs25531 marker on cognitive performance among healthy older adults. In the present study, we addressed this issue in 84 healthy older adults genotyped for biallelic and triallelic variants of 5-HTT.

Neuronal fiber bundle lengths in healthy adult carriers of the ApoE4 allele: a quantitative tractography DTI study.

The epsilon 4 (e4) isoform of apolipoprotein E (ApoE) is a known genetic risk factor for suboptimal brain health. Morphometry studies of brains with Alzheimer's disease have reported significant alterations in temporal lobe brain structure of e4 carriers, yet it remains unclear if the presence of an e4 allele is associated with alterations in the microstructure of white matter fiber bundles in healthy populations. The present study used quantitative tractography based on diffusion tensor imaging (qtDTI) to examine the influence of the e4 allele on temporal lobe fiber bundle lengths (FBLs) in 64 healthy older adults with at least one e4 allele (carriers, N = 23) versus no e4 allele (non-carriers, N = 41).

Association between serotonin transporter promoter polymorphisms and psychological distress in a diabetic population.

Investigations into serotonin transporter and anxiety and depression have shown an association between stress, depression onset and genotype. We investigated the relationship between 5-HTTLPR genotype and depression and anxiety in a population with diabetes mellitus, a condition associated with high rates of stress and depression. Participants were classified according to 'S' and 'L' alleles as well as the modification of the single nucleotide polymorphism (SNP) rs25531.

Preliminary evidence of the short allele of the serotonin transporter gene predicting poor response to cognitive behavior therapy in posttraumatic stress disorder.

Objective: This study was intended to assess the extent to which the low-expression alleles of the serotonin transporter gene promoter predict poor response to cognitive behavior therapy in patients with posttraumatic stress disorder (PTSD).

Method: Forty-five patients with PTSD underwent an 8-week exposure-based cognitive behavior therapy program and provided mouth swabs or saliva samples to extract genomic DNA and classify individuals according to four allelic forms (S(A), S(G), L(A), L(G)) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in PTSD severity following treatment (n = 45) and 6 months later (n = 42).

A single P-loop glutamate point mutation to either lysine or arginine switches the cation-anion selectivity of the CNGA2 channel.

Cyclic nucleotide-gated (CNG) channels play a critical role in olfactory and visual transduction. Site-directed mutagenesis and inside-out patch-clamp recordings were used to investigate ion permeation and selectivity in two mutant homomeric rat olfactory CNGA2 channels expressed in HEK293 cells. A single point mutation of the negatively charged pore loop (P-loop) glutamate (E342) to either a positively charged lysine or arginine resulted in functional channels, which consistently responded to cGMP, although the currents were generally extremely small.

In vivo somatic delivery of plasmid DNA and retrograde transport to obtain cell-specific gene expression in the central nervous system.

We utilised the retrograde transport machinery of neurones to deliver naked plasmid DNA into the central nervous system. A 5.4-kb fragment of the glycine receptor (GlyR) alpha1 subunit gene was cloned and used to drive the expression of a construct encoding for the enhanced green fluorescent protein (EGFP).

Role of charged residues in coupling ligand binding and channel activation in the extracellular domain of the glycine receptor.

The glycine receptor is a member of the ligand-gated ion channel receptor superfamily that mediates fast synaptic transmission in the brainstem and spinal cord. Following ligand binding, the receptor undergoes a conformational change that is conveyed to the transmembrane regions of the receptor resulting in the opening of the channel pore. Using the acetylcholine-binding protein structure as a template, we modeled the extracellular domain of the glycine receptor alpha1-subunit and identified the location of charged residues within loops 2 and 7 (the conserved Cys-loop).

Cation-selective mutations in the M2 domain of the inhibitory glycine receptor channel reveal determinants of ion-charge selectivity.

Ligand-gated ion channel receptors mediate neuronal inhibition or excitation depending on their ion charge selectivity. An investigation into the determinants of ion charge selectivity of the anion-selective alpha1 homomeric glycine receptor (alpha1 glycine receptor [GlyR]) was undertaken using point mutations to residues lining the extra- and intracellular ends of the ion channel. Five mutant GlyRs were studied.