Etax12^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Etax12^C57BL/6J
• Name: ethanol induced ataxia 12; C57BL/6J
• MGI ID: MGI:6430553
• QTL: Etax12 Location: unknown Genetic Position: Chr14, Syntenic

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:244580

Alcohol use disorders are influenced by many interacting genetic and environmental factors. Highlighting this complexity is the observation that large genome-wide association experiments have implicated many genes with weak statistical support. To overcome the limitations of any single experimental system, the analytical strategy used here was to identify genes that exert common phenotypic effects across multiple experimental systems. Specifically, the authors (1) performed a mouse linkage analysis to identify QTL that influence ethanol-induced ataxia; (2) performed a human genetic association analysis of the mouse-identified loci against ethanol-induced body sway, a phenotype that is not only comparable to the mouse ethanol-ataxia phenotype but is also a genetically influenced endophenotype of alcohol use disorders; (3) performed behavioral genetic experiments in Drosophila showing that fly homologs of GPC5, the member of the glypican gene family implicated by both the human and mouse genetic analyses, influence the flys response to ethanol; and (4) discovered data from the literature demonstrating that the genetically implicated genes expression is not only temporally and spatially consistent with involvement in ethanol-induced behaviors but is also modulated by ethanol. The convergence of these data provides strong support to the hypothesis that GPC5 is involved in cellular and organismal ethanol response and the etiology of alcohol use disorders in humans.

The authors compared locomotor responses to ethanol: body sway in humans, ataxia in mice, and locomotor activity in flies. BXD (C57BL/6J x DBA/2J) recombinant inbred mouse data were retrieved and analyses were performed using the WebQTL (www.genenetwork.org) data and analysis suite. GeneNetwork is an online data repository with integrated computational tools designed to allow users to explore complex genetic networks by integrating data from different sources. The BXD resource (a small subset of the collected data) contains over 2800 measured phenotypes, which were contributed by hundreds of scientists, all linked to genotypes, providing an easily accessible tool to genetically map traits of interest. Phenotypes were selected by searching the BXD phenotype database using the search strings ethanol AND ataxia as well as alcohol AND ataxia, From the returned list of phenotypes, those that described ataxic response to the administration of ethanol were selected for interval mapping. Ethanol-induced ataxia QTL were mapped using the Interval Mapping module. A likelihood ratio statistic (LRS) was calculated for each marker using 1000 permutations. LRS values were converted to the log of the odds (LOD) ratio to be consistent with human genetic reporting norms: LOD = LRS/4.61. All genome coordinates are relative to NCBI Mouse Build 37.

No significant linkages were discovered, but 10 of the 12 phenotypes defined 13 suggestive ethanol-induced ataxia. All suggestive loci had their syntenic human region tested for genetic association to ethanol-induced anterior-posterior body sway (BSA). Using the comparative genomics functions of Ensembl, all human genes syntenic with the mouse loci were identified. Human subjects had been genotyped previously using the Illumina HumanCNV370-Duo genotyping array. Marker SNPs were chosen for analysis based on location within the genomic limits for the genes transcript plus 100 kb flanking the transcription start and stop sites. The authors thus had markers spanning the transcripts of the syntenic genes plus possible regulatory sequences flanking the transcribed DNA. Each marker SNP was tested for association to BSA using a regression model. False discovery rate q-values were calculated by treating each syntenic locus as a separate hypothesis. The results for each marker are presented in supporting information, Table S1, and the top associated markers are presented in Table 2.

GPC5 (glypican 5) became the gene of interest due to the statistical strength of the linkage data in mice and the association data in humans. The BXD linkage yielded a LOD score of 3.9 (P = 1.25 x 10^-5), slightly shy of the genome-wide significance value of 4.3 (P = 5.0 x 10^-6). Similarly, the multiple test corrected significance value for association to BSA was q = 0.08 (nominal P = 7.54 x 10^-5) very close to the standard q = 0.05 threshold for significance. Taken together, these data implicate GPC5 as a candidate QTL that influences ethanol-induced ataxia.

* Curator note: It is MGI policy to not create QTL for statistically suggestive QTL. However, since a suggestive QTL identified in this manuscript has been associated with a likely candidate gene, we have made an exception and created an associated QTL. *

Etax12 (ethanol induced ataxia 12) maps to Chr 14 with a peak LOD score of 3.88. Gpc5 has been implicated as a likely candidate gene for Etax12.

References

• Original: J:244580 Joslyn G, et al., Glypican Gene GPC5 Participates in the Behavioral Response to Ethanol: Evidence from Humans, Mice, and Fruit Flies. G3 (Bethesda). 2011 Dec;1(7):627-35
• All: 1 reference(s)