The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression

The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P=0.005, n=19) or schizophrenia (P=0.02, n=36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P=0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P=0.03) and reduced lymphoblastoid and hippocampal KMO expression (P0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.Molecular Psychiatry advance online publication, 5 March 2013; doi:10.1038/mp.2013.11

Forced subduction initiation recorded in the sole and crust of the Semail Ophiolite of Oman

Subduction zones are unique to Earth and fundamental in its evolution, yet we still know little about the causes and mechanisms of their initiation. Numerical models show that far-field forcing may cause subduction initiation at weak pre-existing structures, while inferences from modern subduction zones suggest initiation through spontaneous lithospheric gravitational collapse. For both endmembers, the timing of subduction inception corresponds with initial lower plate burial, whereas coeval or delayed extension in the upper plate are diagnostic of spontaneous or forced subduction initiation, respectively. In modern systems, the earliest extension-related upper plate rocks are found in forearcs, but lower plate rocks that recorded initial burial have been subducted and are inaccessible. Here, we investigate a fossil system, the archetypal Semail Ophiolite of Oman, which exposes both lower and upper plate relics of incipient subduction stages. We show with Lu–Hf and U–Pb geochronology of the lower and upper plate material that initial burial of the lower plate occurred before 104 million years ago, predating upper plate extension and the formation of Semail oceanic crust by at least 8 Myr. Such a time lag reveals far-field forced subduction initiation and provides unequivocal, direct evidence for a subduction initiation mechanism in the geological record