Additive genetic variation in schizophrenia risk is shared by populations of African and European descent

Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope (Pomnibus = 6.9 × 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)--but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional Pomnibus = 2.2 × 10(-33)) and 74 (conditional Pomnibus = 1.1 × 10(-8)). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 × 10(-6)) and HLA-DPβ1 (Phe9, conditional P = 3.0 × 10(-5)) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC

Introgression of a major QTL from an inferior into a superior population using genomic selection

<p>Abstract</p> <p>Background</p> <p>Selection schemes aiming at introgressing genetic material from a donor into a recipient line may be performed by backcross-breeding programs combined with selection to preserve the favourable characteristics of the donor population. This stochastic simulation study investigated whether genomic selection can be effective in preserving a major quantitative trait locus (QTL) allele from a donor line during the backcrossing phase.</p> <p>Methods</p> <p>In a simulation study, two fish populations were generated: a recipient line selected for a production trait and a donor line characterized by an enhanced level of disease resistance. Both traits were polygenic, but one major QTL affecting disease resistance was segregating only within the donor line. Backcrossing was combined with three types of selection (for total merit index) among the crossbred individuals: classical selection, genomic selection using genome-wide dense marker maps, and gene-assisted genomic selection. It was assumed that production could be observed directly on the selection candidates, while disease resistance had to be inferred from tested sibs of the selection candidates.</p> <p>Results</p> <p>Classical selection was inefficient in preserving the target QTL through the backcrossing phase. In contrast, genomic selection (without specific knowledge of the target QTL) was usually effective in preserving the target QTL, and had higher genetic response to selection, especially for disease resistance. Compared with pure genomic selection, gene-assisted selection had an advantage with respect to disease resistance (28–40% increase in genetic gain) and acted as an extra precaution against loss of the target QTL. However, for total merit index the advantage of gene-assisted genomic selection over genomic selection was lower (4–5% increase in genetic gain).</p> <p>Conclusion</p> <p>Substantial differences between introgression programs using classical and genomic selection were observed, and the former was generally inferior with respect to both genetic gain and the ability to preserve the target QTL. Combining genomic selection with gene-assisted selection for the target QTL acted as an extra precaution against loss of the target QTL and gave additional genetic gain for disease resistance. However, the effect on total merit index was limited.</p

Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata

C1 - Journal Articles RefereedAIMS: Increased sympathetic tone in obstructive sleep apnoea results from recurrent episodes of systemic hypoxia and hypercapnia and might be an important contributor to the development of cardiovascular disease. In this study, we re-evaluated the role of a specific population of sympathoexcitatory catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata in the control of sympathetic vasomotor tone, arterial blood pressure, and hypercapnia-evoked sympathetic and cardiovascular responses. METHODS AND RESULTS: In anaesthetized rats in vivo and perfused rat working heart brainstem preparations in situ, C1 neurones were acutely silenced by application of the insect peptide allatostatin following cell-specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor. In anaesthetized rats with denervated peripheral chemoreceptors, acute inhibition of 50% of the C1 neuronal population resulted in ∼50% reduction in renal sympathetic nerve activity and a profound fall in arterial blood pressure (by ∼25 mmHg). However, under these conditions systemic hypercapnia still evoked vigorous sympathetic activation and the slopes of the CO(2)-evoked sympathoexcitatory and cardiovascular responses were not affected by inhibition of C1 neurones. Inhibition of C1 neurones in situ resulted in a reversible fall in perfusion pressure and the amplitude of respiratory-related bursts of thoracic sympathetic nerve activity. CONCLUSION: These data confirm a fundamental physiological role of medullary catecholaminergic C1 neurones in maintaining resting sympathetic vasomotor tone and arterial blood pressure. However, C1 neurones do not appear to mediate sympathoexcitation evoked by central actions of CO(2)

A Dual Infection Pseudorabies Virus Conditional Reporter Approach to Identify Projections to Collateralized Neurons in Complex Neural Circuits

Replication and transneuronal transport of pseudorabies virus (PRV) are widely used to define the organization of neural circuits in rodent brain. Here we report a dual infection approach that highlights connections to neurons that collateralize within complex networks. The method combines Cre recombinase (Cre) expression from a PRV recombinant (PRV-267) and Cre-dependent reporter gene expression from a second infecting strain of PRV (PRV-263). PRV-267 expresses both Cre and a monomeric red fluorescent protein (mRFP) fused to viral capsid protein VP26 (VP26-mRFP) that accumulates in infected cell nuclei. PRV-263 carries a Brainbow cassette and expresses a red (dTomato) reporter that fills the cytoplasm. However, in the presence of Cre, the dTomato gene is recombined from the cassette, eliminating expression of the red reporter and liberating expression of either yellow (EYFP) or cyan (mCerulean) cytoplasmic reporters. We conducted proof-of-principle experiments using a well-characterized model in which separate injection of recombinant viruses into the left and right kidneys produces infection of neurons in the renal preautonomic network. Neurons dedicated to one kidney expressed the unique reporters characteristic of PRV-263 (cytoplasmic dTomato) or PRV-267 (nuclear VP26-mRFP). Dual infected neurons expressed VP26-mRFP and the cyan or yellow cytoplasmic reporters activated by Cre-mediated recombination of the Brainbow cassette. Differential expression of cyan or yellow reporters in neurons lacking VP26-mRFP provided a unique marker of neurons synaptically connected to dual infected neurons, a synaptic relationship that cannot be distinguished using other dual infection tracing approaches. These data demonstrate Cre-enabled conditional reporter expression in polysynaptic circuits that permits the identification of collateralized neurons and their presynaptic partners

Pain, psychological distress and health-related quality of life at baseline and 3 months after radical prostatectomy

BACKGROUND: Inadequate management of postoperative pain is common, and postoperative pain is a risk factor for prolonged pain. In addition to medical and technical factors, psychological factors may also influence the experience of postoperative pain. METHODS: Pain was measured postoperatively at 24, 48, and 72 hr in hospital and after 3 months at home in 140 patients undergoing radical prostatectomy (RP). Patients answered questionnaires about anxiety and depression (HAD scale) and health-related quality of life (SF-36) at baseline and 3 months after surgery. RESULTS: In the first 3 postoperative days, mild pain was reported by 45 patients (32%), moderate pain by 64 (45%), and severe pain by 31 (22%) on one or more days. High postoperative pain scores were correlated with length of hospital stay and with high pain scores at home. Forty patients (29%) reported moderate (n = 35) or severe (n = 5) pain after discharge from hospital. Patients who experienced anxiety and depression preoperatively had higher postoperative pain scores and remained anxious and depressed 3 months after surgery. The scores for the physical domains in the SF-36 were decreased, while the mental health scores were increased at 3 months. Anxiety and depression were negatively correlated with all domains of the SF-36. CONCLUSION: There is a need for nurses to be aware of the psychological status of RP patients and its impact upon patients' experience of postoperative pain and recovery. The ability to identify patients with psychological distress and to target interventions is an important goal for future research

Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation

Transitions at CpG dinucleotides, referred to as “CpG substitutions”, are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates

Autonomic and muscular responses and recovery to one-hour laboratory mental stress in healthy subjects

<p>Abstract</p> <p>Background</p> <p>Stress is a risk factor for musculoskeletal pain. We wanted to explore stress related physiology in healthy subjects in order to gain insight into mechanisms of pain development which may relate to the pathophysiology of musculoskeletal pain disorders.</p> <p>Methods</p> <p>Continuous blood pressure, heart rate, finger skin blood flow, respiration, surface electromyography together with perception of pain, fatigue and tension were recorded on 35 healthy women and 9 healthy men before, during a 60 minute period with task-related low-grade mental stress, and in the following 30 minute rest period.</p> <p>Results</p> <p>Subjects responded physiologically to the stressful task with an increase in trapezius and frontalis muscle activity, increased blood pressure, respiration frequency and heart rate together with reduced finger skin blood flow. The blood pressure response and the finger skin blood flow response did not recover to baseline values during the 30-minute rest period, whereas respiration frequency, heart rate, and surface electromyography of the trapezius and frontalis muscles recovered to baseline within 10 minutes after the stressful task. Sixty-eight percent responded subjectively with pain development and 64% reported at least 30% increase in pain. Reduced recovery of the blood pressure was weakly correlated to fatigue development during stress, but was not correlated to pain or tension.</p> <p>Conclusion</p> <p>Based on a lack of recovery of the blood pressure and the acral finger skin blood flow response to mental stress we conclude that these responses are more protracted than other physiological stress responses.</p