Background To obtain a systematic overview of genes, which may serve therapeutic targets, the CHDI Foundation has recently established the HD Research Crossroads database (http://www.hdresearchcrossroads.org/). With currently over 800 genes, this resource constitutes the most extensive curation of genes relevant to HD, and provides us with an unprecedented opportunity to survey molecular mechanisms involved in HD.
Aims Our aims are (1) to obtain a comprehensive overview of therapeutic targets for HD, their functions and associated pathways as well as (2) to identify potential novel disease-relevant mechanisms.
Methods We have carried out a variety of bioinformatical and statistical analyses to scrutinise genes curated in the HD Crossroads. For selected processes, we also analysed differential expression, using published microarray data. Additionally, we generated a candidate set of novel genetic modifiers of HD by combining information from the HD Crossroads with previous genome-wide linkage studies.
Results Our analyses led to a comprehensive identification of molecular mechanisms associated with HD. Remarkably, we not only recovered processes and pathways, which have frequently been linked to HD (such as cytotoxicity, apoptosis, and calcium signalling), but also found strong indications for other potentially disease-relevant mechanisms that have been less intensively studied in the context of HD (such as the cell cycle and RNA splicing, as well as Wnt and ErbB signalling). For follow-up studies, we provide a compendium of molecular mechanisms that are associated with HD. Additionally, we derived a candidate set of 24 novel genetic modifiers. Details can be obtained at http://hd.sysbiolab.eu.
Conclusions Our analyses can be seen as a first step towards a comprehensive list of biological processes, molecular functions, and pathways involved in HD, and may provide a basis for the development of more holistic disease models and new therapeutics.
- Therapeutic target genes
- molecular pathways
- genetic modifier