A genomic pathway approach to a complex disease: axon guidance and Parkinson disease.

摘要: While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has discovery common gene variations that predispose to complex diseases. The single variants shown associate reproducibly with diseases typically small effect sizes or attributable risks. However, joint actions within pathways may play a role predisposing (the paradigm genetics). goal this study was determine whether polymorphism candidate pathway (axon guidance) predisposed disease (Parkinson [PD]). We mined whole-genome association dataset and identified nucleotide polymorphisms (SNPs) were axon-guidance genes. then constructed models SNPs predicted three outcomes: PD susceptibility (odds ratio = 90.8, p 4.64 × 10−38), survival free (hazards 19.0, 5.43 10−48), age at onset (R2 0.68, 1.68 10−51). By contrast, from thousands random selections genomic outcomes poorly. Mining second mining an expression profiling also supported for many genes PD. These findings could important implications regarding pathogenesis This approach offer insights into other such as Alzheimer disease, diabetes mellitus, nicotine alcohol dependence, several cancers.