Alterations in Task-Related Brain Activation in Children, Adolescents and Young Adults at Familial High-Risk for Schizophrenia or Bipolar Disorder - A Systematic Review.

Children, adolescents, and young adults with at least one first-degree relative [familial high-risk (FHR)] with either schizophrenia (SZ) or bipolar disorder (BD) have a one-in-two risk of developing a psychiatric disorder. Here, we review functional magnetic resonance imaging (fMRI) studies which examined task-related brain activity in young individuals with FHR-SZ and FHR-BD. A systematic search identified all published task-related fMRI studies in children, adolescents, and young adults below an age of 27 years with a first-degree relative with SZ or BD, but without manifest psychotic or affective spectrum disorder themselves. The search identified 19 cross-sectional fMRI studies covering four main cognitive domains: 1) working memory (n = 3), 2) cognitive control (n = 4), 3) reward processing (n = 3), and 4) emotion processing (n = 9). Thirteen studies included FHR-BD, five studies included FHR-SZ, and one study included a pooled FHR group. In general, task performance did not differ between the respective FHR groups and healthy controls, but 18 out of the 19 fMRI studies revealed regional alterations in task-related activation. Brain regions showing group differences in peak activation were regions associated with the respective task domain and showed little overlap between FHR-SZ and FHR-BD. The low number of studies, together with the low number of subjects, and the substantial heterogeneity of employed methodological approaches within the domain of working memory, cognitive control, and reward processing impedes finite conclusions. Emotion processing was the most investigated task domain in FHR-BD. Four studies reported differences in activation of the amygdala, and two studies reported differences in activation of inferior frontal/middle gyrus. Together, these studies provide evidence for altered brain processing of emotions in children, adolescents, and young adults at FHR-BD. More studies of higher homogeneity, larger sample sizes and with a longitudinal study design are warranted to prove a shared or specific FHR-related endophenotypic brain activation in young first-degree relatives of individuals with SZ or BD, as well as to pinpoint specific alterations in brain activation during cognitive-, emotional-, and reward-related tasks

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Publisher Copyright: © 2022, The Author(s).Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.Peer reviewe

The Danish High Risk and Resilience Study-VIA 11: Study Protocol for the First Follow-Up of the VIA 7 Cohort -522 Children Born to Parents With Schizophrenia Spectrum Disorders or Bipolar Disorder and Controls Being Re-examined for the First Time at Age 11.

Introduction: Offspring of parents with severe mental illness have an increased risk of developing mental illnesses themselves. Familial high risk cohorts give a unique opportunity for studying the development over time, both the illness that the individual is predisposed for and any other diagnoses. These studies can also increase our knowledge of etiology of severe mental illness and provide knowledge about the underlying mechanisms before illness develops. Interventions targeting this group are often proposed due to the potential possibility of prevention, but evidence about timing and content is lacking. Method: A large, representative cohort of 522 7-year old children born to parents with schizophrenia, bipolar disorder or controls was established based on Danish registers. A comprehensive baseline assessment including neurocognition, motor functioning, psychopathology, home environment, sociodemographic data, and genetic information was conducted from January 1, 2013 to January 31, 2016. This study is the first follow-up of the cohort, carried out when the children turn 11 years of age. By assessing the cohort at this age, we will evaluate the children twice before puberty. All instruments have been selected with a longitudinal perspective and most of them are identical to those used at inclusion into the study at age 7. A diagnostic interview, motor tests, and a large cognitive battery are conducted along with home visits and information from teachers. This time we examine the children's brains by magnetic resonance scans and electroencephalograms. Measures of physical activity and sleep are captured by a chip placed on the body, while we obtain biological assays by collecting blood samples from the children. Discussion: Findings from the VIA 7 study revealed large variations across domains between children born to parents with schizophrenia, bipolar and controls, respectively. This study will further determine whether the children at familial risk reveal delayed developmental courses, but catch up at age 11, or whether the discrepancies between the groups have grown even larger. We will compare subgroups within each of the familial high risk groups in order to investigate aspects of resilience. Data on brain structure and physical parameters will add a neurobiological dimension to the study

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Genome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants.Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.Clinical epidemiolog

Oxidation/reduction explains heterogeneity of pancreatic somatostatin

AbstractSomatostatin 14 (SS 14) has been isolated from pancreatic extracts, but open gel filtration immunoreactive SS often elutes in two peaks. We isolated both peaks, but upon sequence analysis only authentic SS 14 could be identified. By further gel filtration experiments it turned out that both synthetic and extractable SS appeared homogeneous at neutral pH 7.5, but showed an additional earlier peak in acetic acid. After addition of mercaptoethanol, all of the SS eluted at this earlier position regardless of the pH. We conclude that partial reduction/oxidation of SS explains the heterogeneity

Human colon produces fully processed glucagon-like peptide-1 (7-36 amide).

AbstractThe human colon contains many open-type endocrine cells which express the preproglucagon gene and possess glucagon-like peptide-1 (GLP-1) immunoreactivity, but the molecular form of the peptide is unknown. Acid ethanol extracts of human colon (n = 4) were subjected to gel filtration and successive purification by high-pressure liquid chromatography, monitored by specific RIAs. A single GLP-1-immunoreactive peak was isolated and identified as GLP-1 (7–36)amide by amino acid sequence analysis and mass spectrometry. We conclude that proglucagon is processed in the large intestine in the same manner as in the small intestine, and results in the formation of fully processed biologically active GLP-1