BMC Bioinformatics

, 15:P12 | Cite as

Ttn as a likely causal gene for QTL of alcohol preference on mouse chromosome 2

  • Lishi Wang
  • Yan Jiao
  • Yue Huang
  • Beth Bennett
  • Robert W Williams
  • Dawei Li
  • Hongyu Zhao
  • Joel Gelernter
  • Henry R Kranzler
  • Lindsay A Farrer
  • Weikuan Gu
Open Access
Poster presentation

Keywords

Quantitative Trait Locus Candidate Gene Muscle Protein Causal Gene Mouse Chromosome 

Background

Many quantitative trait loci (QTL) influencing mouse model phenotypes for alcoholism have been mapped genetically. However, the gene(s) comprising the QTL (QTG) are largely unknown. In previous work, Bennett and colleagues created congenic strains carrying the DBA/2IBG (D2) region for alcohol preference (AP) on chromosome 2, on a C57BL/6IBG (B6) background [1]. Subsequently, interval specific congenic recombinant strains (ISCRS), in which the full D2 QTL region was broken into smaller, partially overlapping regions of introgression, were generated and tested. With information from two ISCRS, the QTL has been mapped onto mouse chromosome 2 (Chr2) in a region of 3.4Mb by using C57BL/6J (B6) x DBA/2J (D2) recombinant inbred (RI) strains as well as by using F2 populations. Several candidate genes, Gad1, Atp5g3, Atf2, Sp3 and Sp9, have been evaluated but none of them has been confirmed for a definitive role in the regulation of the QTL of AP on Chr2 [2, 3].

Materials and methods

We have been searching candidate genes for this QTL intensively by using an integrative approach including: 1) bioinformatics tools to search potential functionally relevant genes of alcohol preference within the QTL region [4]; 2) searching for single nucleotide polymorphisms (SNPs) within the exons of every gene between B6 and D2 in the QTL region; 3) conducting real time PCR to examine the differentially expressed genes between B6 and alcohol preferred interval-specific congenic recombinant strains (ISCRS); and 4) analysis of the association of candidate genes in the human population.

Results

Titin (Ttn) is known as a giant muscle protein expressed in the cardiac and skeletal muscles. However, its expression level in the tongue is known to be higher than that in the heart. We therefore investigated if Ttn plays a role in the regulation of AP. Our data indicated that 1) the expression level of Ttn in the less AP congenic strains is significantly higher than that in B6; 2) the expression of a Ttn probe in the BXD RI strains is negatively correlated to that of AP; 3) One SNP is up- and the other is down-stream of Ttn. The alcohol consumption of the B6 genotype is significantly higher than that of D2 genotype in the BXD RI strains, based on data from multiple reports using two-bottles of choice; and 4) the polymorphism of TTN in the human population is highly associated with alcoholism.

Conclusions

We conclude that Ttn is likely a causal gene for the QTL on Ch2 for the AP.

Notes

Acknowledgements

Research supported by the National Institutes of Health, United States (research grants #AA016342, #DA12849, #DA12690, #AA017535, #AA12870, and #AA11330). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). Dr. Kranzler has been a paid consultant for Alkermes, Lilly, Lundbeck, Pfizer, and Roche. He also reports associations with Eli Lilly, Janssen, Schering Plough, Lundbeck, Alkermes, GlaxoSmithKline, Abbott, and Johnson & Johnson, as these companies provide support to the ACNP Alcohol Clinical Trials Initiative (ACTIVE) and Dr. Kranzler has received honoraria from ACTIVE. The other authors report no financial interests or potential conflicts of interest.

References

  1. 1.
    Bennett B, Beeson M, Gordon L, Carosone-Link P, Johnson TE: Genetic dissection of quantitative trait loci specifying sedative/hypnotic sensitivity to ethanol: mapping with interval-specific congenic recombinant lines. Alcohol Clin Exp Res. 2002, 26 (11): 1615-1624. 10.1111/j.1530-0277.2002.tb02463.x.CrossRefPubMedGoogle Scholar
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    Wang LS, Jiao Y, Huang Y, Liu XY, Gibson G, Bennett B, Hamre KM, Li DW, Zhao HY, Gelernter J, Kranzler HR, Farrer LA, Lu L, Wang YJ, Gu WK: Critical evaluation of transcription factor Atf2 as a candidate modulator of alcohol preference in mouse and human populations. Genet Mol Res. 2013, 12 (4): 5992-6005. 10.4238/2013.November.26.9.PubMedCentralCrossRefPubMedGoogle Scholar
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Copyright information

© Wang et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Lishi Wang
    • 1
    • 2
  • Yan Jiao
    • 1
  • Yue Huang
    • 1
  • Beth Bennett
    • 3
  • Robert W Williams
    • 4
  • Dawei Li
    • 5
  • Hongyu Zhao
    • 6
    • 7
  • Joel Gelernter
    • 5
    • 7
    • 8
    • 9
  • Henry R Kranzler
    • 10
    • 11
  • Lindsay A Farrer
    • 12
  • Weikuan Gu
    • 1
  1. 1.Department of Orthopaedic Surgery & BME - Campbell Clinic and PathologyUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Basic Medical ResearchInner Mongolia Medical UniversityHohhot CityChina
  3. 3.Department of PharmacologyUniversity of Colorado DenverAuroraUSA
  4. 4.Department of Anatomy and NeurobiologyUniversity of Tennessee Health Science CenterMemphisUSA
  5. 5.Department of PsychiatrySchool of Medicine, Yale UniversityNew HavenUSA
  6. 6.Department of Epidemiology and Public HealthSchool of Medicine, Yale UniversityNew HavenUSA
  7. 7.Department of GeneticsSchool of Medicine, Yale UniversityNew HavenUSA
  8. 8.VA Connecticut Healthcare CenterWest HavenUSA
  9. 9.Department of NeurobiologyYale University School of MedicineNew HavenUSA
  10. 10.Department of PsychiatryUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  11. 11.VISN 4 MIRECCPhiladelphia VAMCPhiladelphiaUSA
  12. 12.Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Genetics & Genomics, Biostatistics, and EpidemiologyBoston University Schools of Medicine and Public HealthBostonUSA

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