ABSTRACT
Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1ß and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.
Subject(s)
Bipolar Disorder/genetics , Kynurenic Acid/metabolism , Psychotic Disorders/genetics , Adult , Aged , Bipolar Disorder/cerebrospinal fluid , Bipolar Disorder/metabolism , Brain/metabolism , Chromosomes, Human, Pair 1/genetics , Cognition Disorders/complications , Cognitive Dysfunction/genetics , Cognitive Dysfunction/metabolism , Female , Genome-Wide Association Study , Humans , Kynurenic Acid/cerebrospinal fluid , Male , Middle Aged , Psychotic Disorders/complications , Psychotic Disorders/metabolism , Sorting Nexins/geneticsABSTRACT
In this study we have evaluated the concordance between serology, using five commercially available antibody assays designed to discriminate between HIV-1 and HIV-2, and the polymerase chain reaction (PCR) for the detection of HIV-1 and HIV-2 dual infection. Thirty-seven HIV-1 and HIV-2 dually reactive serum samples from individuals in Guinea-Bissau with total CD4+ T lymphocyte counts ranging from 9 to 948 x 10(6)/liter were included in the study. All samples were tested by Multispot, Pepti-LAV, and Immunocomb HIV-1 and HIV-2 discriminatory antibody assays. Thirty-two of the 37 samples were also tested by a combination of two HIV type-specific antibody enzyme-linked immunosorbent assays (ELISA; Wellcozyme HIV-1 and Murex HIV-2). Each sample showed dual reactivity in all or any of these assays. A nested PCR based on primer systems in the vif and pol regions of HIV-1 and in the gag and LTR regions of HIV-2 was used to evaluate the serological results. Thirty samples from HIV-1 antibody-positive individuals and 30 samples from HIV-2 antibody-positive individuals were all PCR positive with their corresponding primer systems. The type specificity was 100% for all of the primer systems. The concordance between dual HIV-1 and HIV-2 reactivity on the serological assays and PCR was 77.7% for Multispot, 80% for Pepti-LAV, 81.8% for Immunocomb, and 85.7% for the two ELISAs used in combination. Thus the majority of individuals included in this study appeared to be truly dually infected. The study shows that it is possible, through a careful selection of assays, to reach a high concordance between serological assays and PCR in studying HIV-1 and HIV-2 dual infections.
