A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

Abstract

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R 2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes

“…A Volcano plot was used to identify differentially expressed genes by comparing the SNCA duplication carrier in triplicate to the controls, using a ≥1.2-fold change and p<0.05 as the significance threshold (Welch's t-test). Furthermore, we compared our results with the significantly deregulated genes (p<0.05 t-test) from (i) an Affymetrix transcriptomic analysis of PBMCs between 50 PD patients and 22 controls from the GEO dataset GDS2519 (www.ncbi.nlm.nih.gov/sites/gds) (Scherzer et al, 2007) and (ii) an Affymetrix transcriptomic analysis of substantia nigra between 16 PD patients and 9 controls from the GEO dataset GDS2821 (Lesnick et al, 2007).…”

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

“…Pathway-based analyses of genomic data may offer several advantages over traditional genetic association analyses: First, by increasing study power if, as has been suggested, the joint action of common variants within pathways have a major role in predisposing to complex genetic disorders. 6 Second, by being robust to the influence that differences in linkage disequilbrium (LD) (for example, between study populations or SNP arrays) may have on identification of associated variants. Third, by providing additional information related to function over and above the statistical SNP genome-wide association study (GWAS) data; that is, implicating a molecular pathway in a disease process may be more biologically informative than interpreting involvement of an anonymous genetic marker.…”

“…A number of formal pathway-based analytical methods have been described previously [6][7][8][9][10][11] and are reviewed elsewhere. 9,12 In this study, we used the SNP ratio test (SRT) 10 for the following reasons.…”

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

“…sigma-1 receptor | p35 | myristic acid | axon growth | cdk5 A xons are structurally and functionally distinct protrusions of neurons that modulate neurotransmitter release and neural function. Malfunction of axonal maintenance, regeneration, and target recognition contribute to CNS disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke, and spinal cord injuries (1)(2)(3). Cyclin-dependent kinase (Cdk) 5 activities within the axon play a significant role in the cytoskeletal dynamics of microtubules and actin neurofilaments (NFs), which determine axonal path and length.…”