William E. Bunney

Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry

Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects ≈1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 × 10−6. We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P ≈ 10−7: 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 × 10−7) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.

DNA microarray analysis of functionally discrete human brain regions reveals divergent transcriptional profiles

Transcriptional profiles within discrete human brain regions are likely to reflect structural and functional specialization. Using DNA microarray technology, this study investigates differences in transcriptional profiles of highly divergent brain regions (the cerebellar cortex and the cerebral cortex) as well as differences between two closely related brain structures (the anterior cingulate cortex and the dorsolateral prefrontal cortex). Replication of this study across three independent laboratories, to address false-positive and false-negative results using microarray technology, is also discussed. We find greater than a thousand transcripts to be differentially expressed between cerebellum and cerebral cortex and very few transcripts to be differentially expressed between the two neocortical regions. We further characterized transcripts that were found to be specifically expressed within brain regions being compared and found that ontological classes representing signal transduction machinery, neurogenesis, synaptic transmission, and transcription factors were most highly represented.

Sample matching by inferred agonal stress in gene expression analyses of the brain

BackgroundGene expression patterns in the brain are strongly influenced by the severity and duration of physiological stress at the time of death. This agonal effect, if not well controlled, can lead to spurious findings and diminished statistical power in case-control comparisons. While some recent studies match samples by tissue pH and clinically recorded agonal conditions, we found that these indicators were sometimes at odds with observed stress-related gene expression patterns, and that matching by these criteria still sometimes results in identifying case-control differences that are primarily driven by residual agonal effects. This problem is analogous to the one encountered in genetic association studies, where self-reported race and ethnicity are often imprecise proxies for an individuals actual genetic ancestry.ResultsWe developed an Agonal Stress Rating (ASR) system that evaluates each samples degree of stress based on gene expression data, and used ASRs in post hoc sample matching or covariate analysis. While gene expression patterns are generally correlated across different brain regions, we found strong region-region differences in empirical ASRs in many subjects that likely reflect inter-individual variabilities in local structure or function, resulting in region-specific vulnerability to agonal stress.ConclusionVariation of agonal stress across different brain regions differs between individuals, revealing a new level of complexity for gene expression studies of brain tissues. The Agonal Stress Ratings quantitatively assess each samples extent of regulatory response to agonal stress, and allow a strong control of this important confounder.

Dorsolateral Prefrontal Cortical Parallel Circuit in Schizophrenia: Postmortem Abnormalities

Emerging evidence from postmortem studies in schizophrenics implicate disturbances in the dorsolateral prefrontal parallel circuit, specifically in the dorsolateral prefrontal cortex (DLPFC) and mediodorsal nucleus (MD) of the thalamus. Cognitive deficits in schizophrenia include impairments in working memory that are accompanied by test-related decreases in DLPFC activation. The DLPFC is part of the dorsolateral prefrontal cortical parallel circuit, one of three cognitive-affective circuitries. Postmortem evidence for abnormalities in the DLPFC of schizophrenics include abnormal cell settling patterns of interstitial neurons in the white matter, reductions in GAD mRNA, and decreases in γ-2 mRNA of the γ-2 GABA-A receptor subunit as compared to matched controls. The DLPFC has substantial projections to the MD nucleus. Studies in schizophrenics reveal dramatic reductions in neuronal number of the MD with evidence of defects in the MD thalamic subnuclei (i.e., densocellular and parvocellular subnuclei) that project to the DLPFC. Some neuropathological abnormalities in the DLPFC and MD nucleus of schizophrenics could be attributed to disturbances in early cortical development. The neurodevelopmental hypothesis of schizophrenia is supported by the finding that three populations of cortical subplate markers (nicotinamide-adenine dinucleotide phosphate diaphorase, NADPH-d, microtubular-associated protein-2, MAP-2 and a monoclonal antibody that represents a non-phosphorylated neurofilament protein, SMI-32, a 160–200kDA protein), are abnormally distributed in the interstitial white matter of the DLPFC in patients. Disturbances in early neurodevelopment could occur during a period of genetic/environmental vulnerability, most likely in the second trimester, when large numbers of neurons are migrating from the ventricular zone to their target destinations in the cortex. These disturbances might be reflected in abnormal functioning of neuronal circuitries such as the dorsolateral prefrontal parallel circuit containing the DLPFC and MD nucleus of the thalamus.

Psychobiological Studies of Mania

This paper will review some clinical and biological aspects of mania including symptoms, diagnosis and treatments. Special emphasis will be placed on data which may be relevant to understanding mania such as receptor studies, effects of lithium on behavioral supersensitivity, incidence of tardive dyskinesia in mania, and timedependent changes in vulnerability to the switch. Finally, some newer treatments for mania will be briefly discussed.