Purpose: Compared with white women, black women experience a disproportionate burden of aggressive breast cancer for reasons that remain unknown and understudied. In the first study of its kind, we determined the distribution of molecular subtypes of invasive breast tumors in indigenous black women in West Africa. Patients and Methods: The study comprised 507 patients diagnosed with breast cancer between 1996 and 2007 at six geographic regions in Nigeria and Senegal. Formalin-fixed and paraffin-embedded sections were constructed into tissue microarrays and immunostained with 15 antibodies. Five molecular subtypes were determined, and hierarchical cluster analysis was conducted to explore subgroups for unclassified cases. Results: The mean (± standard deviation) age of 378 patients in the first cohort was 44.8 ± 11.8 years, with the majority of women presenting with large (4.4 ± 2.0 cm) high-grade tumors (83%) in advanced stages (72% node positive). The proportions of estrogen receptor (ER) –positive, progesterone receptor–positive, and human epidermal growth factor receptor 2 (HER2) –positive tumors were 24%, 20%, and 17%, respectively. Triple negativity for these markers was predominant, including basal-like (27%) and unclassified subtype (28%). Other subtypes were luminal A (27%), luminal B (2%), and HER2 positive/ER negative (15%). The findings were replicated in the second cohort of 129 patients. The unclassified cases could be grouped into a bad prognosis branch, with expression of vascular endothelial growth factor, B-cell lymphoma extra-large protein, and Cyclin E, and a good prognosis branch, with expression of B-cell lymphoma protein 2 and Cyclin D1. Conclusion: These findings underscore the urgent need for research into the etiology and treatment of the aggressive molecular subtypes that disproportionately affect young women in the African diaspora.

The subtilisin-like proprotein convertases PC1/3 (SPC3) and PC2 (SPC2) are believed to be the major endoproteolytic processing enzymes of the regulated secretory pathway. They are expressed together or separately in neuroendocrine cells throughout the brain and dispersed endocrine system in both vertebrates and invertebrates. Disruption of the gene-encoding mouse PC1/3 has now been accomplished and results in a syndrome of severe postnatal growth impairment and multiple defects in processing many hormone precursors, including hypothalamic growth hormone-releasing hormone (GHRH), pituitary proopiomelanocortin to adrenocorticotropic hormone, islet proinsulin to insulin and intestinal proglucagon to glucagon-like peptide-1 and -2. Mice lacking PC1/3 are normal at birth, but fail to grow normally and are about 60% of normal size at 10 weeks. They lack mature GHRH, have low pituitary growth hormone (GH) and hepatic insulin-like growth factor-1 mRNA levels and resemble phenotypically the “little” mouse (Gaylinn, B. D., Dealmeida, V. I., Lyons, C. E., Jr., Wu, K. C., Mayo, K. E. & Thorner, M. O. (1999) Endocrinology 140, 5066–5074) that has a mutant GHRH receptor. Despite a severe defect in pituitary proopiomelanocortin processing to mature adrenocorticotropic hormone, blood corticosterone levels are essentially normal. There is marked hyperproinsulinemia but without impairment of glucose tolerance. In contrast, PC2-null mice lack mature glucagon and are chronically hypoglycemic (Furuta, M., Yano, H., Zhou, A., Rouille, Y., Holst, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H. & Steiner, D. (1997) Proc. Natl. Acad. Sci. USA 94, 6646–6651). The PC1/3-null mice differ from a human subject reported with compound heterozygosity for defects in this gene, who was of normal stature but markedly obese from early life. The PC1/3-null mice are not obese. The basis for these phenotypic differences is an interesting topic for further study. These findings prove the importance of PC1/3 as a key neuroendocrine convertase.

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P_bonferroni<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders. Associated genetic and gene expression changes have been identified, but many have not been replicated and have unknown functions. We identified groups of genes whose expressions varied together, that is co-expression modules, then tested them for association with SCZ. Using weighted gene co-expression network analysis, we show that two modules were differentially expressed in patients versus controls. One, upregulated in cerebral cortex, was enriched with neuron differentiation and neuron development genes, as well as disease genome-wide association study genetic signals; the second, altered in cerebral cortex and cerebellum, was enriched with genes involved in neuron protection functions. The findings were preserved in five expression data sets, including sets from three brain regions, from a different microarray platform, and from BD patients. From those observations, we propose neuron differentiation and development pathways may be involved in etiologies of both SCZ and BD, and neuron protection function participates in pathological process of the diseases.

Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in P_meta=9.49 × 10⁻¹² (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08–1.17) across both disorders and P_meta=2.67 × 10⁻⁸ (OR=1.15, 95% CI: 1.08–1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.