Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer's disease, Parkinson's disease, and related disorders

Abstract

The discovery of causative genetic mutations in affected family members has historically dominated our understanding of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility. Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes may be influenced on a personalized basis by a combination of variants - some common and others rare, some protective and others deleterious - in key genes and pathways. Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance clinical translation.

Keywords: Alzheimer’s disease (AD); Neurodegeneration; Parkinson’s disease (PD); biomarker; complex disease; genome-wide association study (GWAS); network; omics; pathway; single nucleotide polymorphism (SNP).

Figure 1

Conceptual model of candidate pathways contributing to neurodegeneration. Candidate pathways influencing the balance of neuronal survival and degeneration are displayed within broader functional groups based on their major site or mode of action (intracellular mechanisms, local tissue environment influences, systemic influences, and mechanisms related to neurodevelopment and aging). The pathways and overarching functional groups in this model are highly related and can have overlapping or interacting components which can collectively modulate neurodegenerative processes.

Figure 2

Regulatory network centered on the SP1 and AP-1 transcription factors is enriched with top AD and PD genes. Meta-analytic genetic association data from public databases and supplementary manual curation was used to generate a list of 13 AD genes and 15 PD genes. Network analysis was performed using MetaCore (GeneGo, Inc.) to relate these input genes to known transcription factors and proximal targets based on published findings. A highly interconnected network including 9 AD genes (labeled in blue), 10 PD genes (labeled in red), and 13 additional genes (labeled in black) was identified. Many of the input AD and PD genes exhibit co-regulation by the SP1 and AP-1 transcription factors. Other genes of interest were also related to input AD and PD genes and represent a variety of candidate pathways in neurodegeneration.

Figure 3

Biological pathways and networks: a hub for convergent omics. Numerous large scale omics approaches are being used to study complex neurodegenerative diseases and endophenotypes in human tissue and animal and other model systems. Unlike individual genes and other isolated molecules, which may not be present in all model systems and may have differential sensitivity for detection with various study designs, pathways and networks are well-conserved and can be evaluated for convergence across diverse methodological approaches. Integration of findings to identify pathways and networks with consistent relationships to disease is likely to enhance the development of diagnostic biomarkers and treatment and prevention strategies.