Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders

PDGF function in diverse neural crest cell populations

Activation of platelet derived growth factor (PDGF) receptors causes context-dependent cellular responses, including proliferation and migration, and studies in model organisms have demonstrated that this receptor family (PDGFRα and PDGFRβ) is required in many mesenchymal and migratory cell populations during embryonic development. One of these migratory cell populations is the neural crest, which forms cranial bone and mesenchyme, sympathetic neurons and ganglia, melanocytes and smooth muscle. Mice with disruption of PDGF signaling exhibit defects in some of these neural crest derivatives including the palate, aortic arch, salivary gland and thymus. Although many of these neural crest defects were identified many years ago, the mechanism of action of PDGF in neural crest remains controversial. In this review, we examine the current knowledge of PDGF function during neural crest cell (NCC) development, focusing on its role in the formation of different neural crest-derived tissues and the implications for PDGF receptors in NCC-related human birth defects

Factors controlling cardiac neural crest cell migration

Cardiac neural crest cells originate as part of the postotic caudal rhombencephalic neural crest stream. Ectomesenchymal cells in this stream migrate to the circumpharyngeal ridge and then into the caudal pharyngeal arches where they condense to form first a sheath and then the smooth muscle tunics of the persisting pharyngeal arch arteries. A subset of the cells continues migrating into the cardiac outflow tract where they will condense to form the aorticopulmonary septum. Cell signaling, extracellular matrix and cell-cell contacts are all critical for the initial migration, pauses, continued migration and condensation of these cells. This Review elucidates what is currently known about these factors