A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease
PLoS Genet 3(6): e98.

Complex diseases are common disorders that are believed to have many causes. Examples include Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers. This study represents a paradigm shift from single gene to pathway studies of complex diseases.

We present the example of Parkinson disease (PD) and a complex array of chemical signals that wires the brain during fetal development (the axon guidance pathway). We mined a dataset that studied hundreds of thousands of DNA variations (single nucleotide polymorphisms [SNPs]) in persons with and without PD and identified SNPs that were assigned to axon-guidance pathway genes. We then identified sets of SNPs that were highly predictive of PD susceptibility, survival free of PD, and age at onset of PD. The effect sizes and the statistical significance observed for the pathway were far greater than for any single gene. We validated our findings for the pathway using a second SNP dataset for PD and also a dataset for PD that studied RNA variations.

There is prior evidence that the axon guidance pathway might play a role in other brain disorders (e.g., Alzheimer disease, Tourette syndrome, dyslexia, epilepsy, and schizophrenia).

A genomic pathway approach may lead to important breakthroughs for many complex diseases.

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