A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Protracted haemangioblastic proliferation and differentiation in von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is caused by germline mutation of the VHL tumour suppressor gene. Patients frequently develop multiple nervous system tumours, denominated haemangioblastomas. Analysis of affected autopsy tissues suggests that tumourigenesis propagates from developmentally arrested, embryonic cells and progresses with consistent architectural, cytological, and molecular sequences similar to haemangioblastic formation and differentiation in the embryo. In this study, we analysed 156 nervous system tumours, 139 of which had been surgically resected from 83 VHL patients. We demonstrate that large tumours consistently contain epithelioid components characteristic of haemangioblastic differentiation in comparison to small tumours that solely display a poorly differentiated, mesenchymal structure. We further show exclusive activation of HIF2alpha in both small mesenchymal tumours and the mesenchymal component of large tumours, whereas activation of HIF1alpha is associated with epithelioid structure. We also show that the MIB1 proliferative index is variably increased in the epithelioid component of large tumours, with extramedullary haematopoiesis foci within the epithelioid component at 100%. These data provide compelling evidence that nervous system tumourigenesis in VHL disease represents a protracted process of haemangioblastic proliferation and differentiation that parallels haemangioblastic formation and differentiation in the embryo.

Epididymal cystadenomas and epithelial tumourlets: effects of VHL deficiency on the human epididymis.

Although epididymal cystadenomas (ECAs) are among the most frequent VHL disease-associated tumours, fundamental questions about their pathogenesis have remained unanswered. Classification of ECAs is controversial, and the cell of origin is unknown. It is also unknown whether ECAs-like other VHL disease-associated tumours-arise as a result of VHL gene inactivation, and whether ECAs exhibit subsequent activation of hypoxia-inducible factor HIF. Moreover, the morphological spectrum of earliest ECA formation is unknown. In a detailed molecular pathological analysis of a series of epididymides collected from VHL patients at autopsy, we found that ECAs are true neoplasms that arise secondary to inactivation of the wild-type copy of the VHL gene, followed by early and simultaneous activation of HIF1 and HIF2 associated with up-regulation of downstream targets, including CAIX and GLUT-1. The observations also indicate that ECA formation evolves from a variety of microscopic epithelial tumourlets, and that these tumourlets are confined to the efferent ductular system. Although genetic and immunohistochemical analysis of precursor structures consistently revealed VHL gene inactivation and activation of HIF in the precursor lesions, only a small subset appears to progress into frank cystadenoma. Thus, ECA tumorigenesis in VHL disease shares fundamental principles with tumorigenesis in other affected organ systems.