Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals cross-diagnostic and diagnosis-specific RNA expression changes in major psychiatric disorders.

Despite strong evidence of heritability and growing discovery of genetic markers for major mental illness, little is known about how gene expression in the brain differs across psychiatric diagnoses, or how known genetic risk factors shape these differences. Here we investigate expressed genes and gene transcripts in postmortem subgenual anterior cingulate cortex (sgACC), a key component of limbic circuits linked to mental illness. RNA obtained postmortem from 200 donors diagnosed with bipolar disorder, schizophrenia, major depression, or no psychiatric disorder was deeply sequenced to quantify expression of over 85,000 gene transcripts, many of which were rare. Case-control comparisons detected modest expression differences that were correlated across disorders. Case-case comparisons revealed greater expression differences, with some transcripts showing opposing patterns of expression between diagnostic groups, relative to controls. The ~250 rare transcripts that were differentially-expressed in one or more disorder groups were enriched for genes involved in synapse formation, cell junctions, and heterotrimeric G-protein complexes. Common genetic variants were associated with transcript expression (eQTL) or relative abundance of alternatively spliced transcripts (sQTL). Common genetic variants previously associated with disease risk were especially enriched for sQTLs, which together accounted for disproportionate fractions of diagnosis-specific heritability. Genetic risk factors that shape the brain transcriptome may contribute to diagnostic differences between broad classes of mental illness.

Single nucleotide polymorphisms in ANKK1 and the dopamine D2 receptor gene affect cognitive outcome shortly after traumatic brain injury: a replication and extension study.

OBJECTIVE: The two objectives of this study were (1) to replicate the previous finding that a single nucleotide polymorphism (SNP) in the ANKK1 gene (SNP rs1800497 formerly known as the DRD2 TAQ1 A allele) is associated with measures of learning and response latency after traumatic brain injury (TBI) and (2) to further characterize the genetic basis of the effect by testing the strength of association and degree of linkage disequilibrium between the cognitive outcome measures and a selected ensemble of 31 polymorphisms from three adjacent genes in the region of rs1800497. METHOD: A cohort of 54 patients with TBI and 21 comparison subjects were genotyped for the DRD2 TAQ1 A polymorphism (rs1800497). Ninety-three patients with TBI and 48 comparison subjects (the current cohort and an earlier independent cohort) were also genotyped for 31 additional neighbouring polymorphisms in NCAM, ANKK1 and DRD2. TBI patients were studied 1 month after injury. All subjects completed memory and attention tests, including the California Verbal Learning Test (CVLT) recognition task and the Gordon Continuous Performance Test (CPT). RESULTS: As in a previous study the T allele of TAQ1 A (rs1800497) was associated with poorer performance on the CVLT recognition trial in both TBI and control subjects. There was also a significant diagnosis-by-allele interaction on CPT measures of response latency, largely driven by slower performance in the TBI participants with the T allele. Analysis of 31 additional neighbouring polymorphisms from NCAM, ANKK1 and DRD2 in the TBI patients showed four haploblocks. A haploblock of three SNPs in ANKK1 (rs11604671, rs4938016 and rs1800497 (TAQ1A)) showed the greatest association with cognitive outcome measures. CONCLUSIONS: The results confirm a previously published association between the TAQ1 A (rs1800497) T allele and cognitive outcome measures 1 month after TBI and suggest that a haploblock of polymorphisms in ANKK1, rather than the adjacent DRD2 gene, has the highest association with these measures after TBI.

A fatal case of postpartum cerebral angiopathy with literature review.

INTRODUCTION: Postpartum cerebral angiopathy (PCA) is a rare and pathophysiologically ill-characterized cerebral vasoconstriction syndrome, occurring within 30 days of a usually uncomplicated pregnancy and delivery. Its onset has been associated with the use of vasoactive medications, particularly ergot alkaloids. Other cases have occurred in the absence of these medications, prompting conjecture into possible overlap between PCA and other conditions known to cause cerebral vasoconstriction, including primary angiitis of the central nervous system and postpartum eclampsia. The vast majority of cases follow a relatively benign course; however, a fatal case has been reported. Histopathologic findings in PCA, so far limited to the fatal case and two more recent biopsies, have been nonspecific. OBJECTIVE: Here we present a second fatal case of PCA, including pre- and post-mortem histopathologic analysis. We also include a review of all PCA cases reported in the English literature. METHODS: Criteria for the clinical diagnosis of PCA are proposed and used to select case reports from the medical literature. Data pertaining to patient characteristics, clinical symptomatology, cerebral imaging findings, and clinical outcomes are compared between cases associated with the postpartum use of vasoactive medications and spontaneous cases. CONCLUSIONS: We conclude that histopathologic findings in PCA are nonspecific and secondary to ischemic brain injury. Functional vasoconstriction is the most likely primary pathophysiologic process in PCA. The etiology in cases associated with medications may be due to idiosyncratic reactions to these agents. Significant overlap in symptomatology and clinical features exists between spontaneous cases and late postpartum eclampsia.