Keeping up with genetic discoveries in amyotrophic lateral sclerosis: The ALSoD and ALSGene databases

Figures & data

Table I. Genes proposed to cause Mendelian forms of ALS.

Gene	Protein	Location	Inheritance	#Mutations	#Patients	Proposed molecular effects/pathogenic relevance
ALS2	amyotrophic lateral sclerosis 2	2q33.1	recessive	19	4	endosome/membrane trafficking
ANG	angiogenin	14q11.1	dominant	18	27	RNAase
DAO	D-amino-acid oxidase	12q24	dominant	1	1	D-serine pathway
FIG4	FIG4 homolog, SAC1 lipid phosphatase domain containing (S. cerevisiae)	6q21	dominant	10	9	Golgi complex maintenance, vesicle trafficking, cell signalling
FUS	fused in sarcoma	16p11.2	both	27	5	RNA processing
NEFH	neurofilament, heavy polypeptide 200kDa, heavy chain	22q12.1-q13.1	?	7	10	axonal transport
OPTN	optineurin	10p13	recessive	3	0	Golgi complex maintenance and membrane trafficking
SETX	senataxin	9q34.13	dominant	4	60	DNA and RNA processing
SOD1	superoxide dismutase 1	21q22.11	both	156	184	toxic aggregation of SOD1; oxidative damage; mitochondrial dysfunction; RNA destabilization; impairment of axonal transport; glutamate excitotoxicity
TARDBP	TAR DNA binding protein (TDP-43)	1p36.22	dominant	38	66	RNA processing
VAPB	VAMP (vesicle-associated membrane protein)-associated protein B and C	20q13.33	dominant	2	19	vesicle trafficking
VCP	valosin-containing protein	9p13	dominant	4	8	ubiquination

For an up-to-date overview of these and other potential Mendelian ALS genes see the ‘ALSoD database’ (http://alsod.iop.kcl.ac.uk). Note that mutations in other genes have also been proposed to cause familial forms of ALS, albeit with inconclusive evidence (see text for more details).

# Mutations = number of mutations reported as ALS-causing; # Patients = number of records on ALS patients submitted to ALSoD that carry mutations in this gene.

Figure 1. ALSoD homepage.

Figure 2. Genotype-phenotype summary for TARDBP (coding for TDP43). Gene summaries are displayed on selection. More detailed customised analyses are also possible allowing specific questions to be asked of the database.

Figure 3. An example of a geographical overview of the mutation distribution of SOD1. Geographical analysis is available for most FALS genes. More sophisticated map overlays are planned.

Figure 4. Gene interactions using a GeneMANIA interface at ALSoD. Potential gene pathways and networks can be explored via the GeneMANIA feature on ALSoD, e.g. by including established or proposed ALS genes in the functional predictions.

Figure 5. Screenshot of the ALSGene homepage (www.alsgene.org).

Figure 6. Summary of ALSGene methodology. Flowchart of data selection, processing and analysis strategies applied for ALSGene. Polymorphisms with non-overlapping data from at least four data sets are subjected to meta-analyses. Significant meta-analysis results are highlighted in a designated section on the ALSGene homepage.

Figure 7. Random-effects meta-analysis of rs12608932 in UNC13A including all published studies (as of 1 March 2011). Example ALSGene forest plot providing a visual summary of meta-analysis results. Study-specific odds allelic ratios (ORs, bottom section) are displayed either as provided in the original publication or calculated de novo from allele or genotype summaries. Black squares represent point estimates of the OR (scaled to sample size), horizontal lines represent 95% confidence intervals. Summary ORs (top section) are then calculated from the study-specific ORs using random effects models for a number of different paradigms. Grey diamonds represent point estimates and 95% confidence intervals of the respective meta-analyses. I² = a measure of between-study heterogeneity (see text for more details). Forest plots are only available for polymorphisms that have data available from four independent data sets.

Figure 8. Example screenshot of a customized UCSC genome-browser track (PDGene database) displaying meta-analysis p-values. The USCS genome-browser (http://genome.ucsc.edu/cgi-bin/hgGateway) presents an up-to-date, easy-to-navigate interface of the human genome. It integrates information from a broad variety of databases (e.g. gene-mapping, expression, evolutionary conservation) at base-pair resolution. Shown is an example screenshot for a customized browser track from the PDGene database maintained by our group (http://www.pdgene.org), which summarizes meta-analysis results (-log(10)) p-values, based on data from both genome-wide and candidate-gene association studies) equivalently at base-pair resolution. SNPs (rs-numbers) displayed in grey are based on meta-analyses of available GWAS datasets, those displayed in blue are supplemented by candidate-gene/replication datasets. All rs-numbers cross-link back to the PDGene database to provide more details on the respective meta-analyses. Note that this feature will become available on ALSGene once initial data entry and analysis is completed.