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  • Original Research Article
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Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus

Molecular Psychiatry volume 9, pages 312–319 (2004)Cite this article

Abstract

Two previous large genetic linkage studies in the US population have implicated an area in chromosome 1p to contain a susceptibility gene for alcohol dependence. The 1-LOD support interval of the linkage signal spans about 30 cM and contains >30 000 000 DNA base pairs (bp) and 700 predicted genes. In order to reduce the size of the candidate area and potentially identify novel candidate genes within this region, we fine-mapped this area using closely spaced short tandem repeat (STR) markers and the transmission disequilibrium test (TDT) in small nuclear families. The subjects were 87 European-American families including one or more alcohol-dependent offspring (93 children and 174 parents). The initial marker set consisted of 30 STR markers, spanning the Marshfield map interval between 101.48 and 130.73 cM. Using the TDTPHASE program, we identified three markers in the distal part of this region (125–126 cM), which showed evidence of transmission disequilibrium. On the basis of this result, an additional 12 STR markers were genotyped in this region; some of these markers provided additional evidence for linkage disequilibrium. The strongest evidence for transmission disequilibrium was obtained at the marker D1S406 (P=0.005, 126.16 cM), with supporting evidence from three neighboring STR markers D1S424 (126.16 cM, P=0.01), D1S2804 (126.16 cM, P=0.04), and D1S2776 (126.16 cM, P=0.02), which are all located within a <350 000 bp interval. These findings suggest that a gene (or genes) causing susceptibility to alcohol dependence resides near location 126.16 cM on chromosome 1. In addition, these results provide independent confirmation of the linkage finding regarding the identification of at least one gene in this region increasing the risk for alcohol dependence.

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Acknowledgements

This work was supported by the National Institutes of Health (K08 AA13732, R01 AA11330, P50 AA12870, M01 RR06192, K02 AA00261, and K24 AA13736), the US Department of Veterans Affairs (VA Alcohol Research Center, VA Mental Illness Research, Education and Clinical Center (VA MIRECC), and VA Veterans Research Enhancement Award Program (VA REAP)), the Alcoholic Beverage Medical Research Foundation (ABMRF), and the Ethel F Donaghue Women's Health Investigator Program at Yale. We also wish to thank the UK Human Genome Mapping Project Resource Center for technical help and proving access to UNPHASED and GLUE. We are thankful to Dr Frank Dudbridge for his many helpful comments. We are grateful to Ms Julie Earle Ray, Mr Greg Dalton-Kay, and Ms Ann Marie Wantroba Lacobelle for technical assistance.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    J Lappalainen, I Petrakis, L K Somberg, J H Krystal & J Gelernter

  2. VA Connecticut Healthcare System, West Haven, CT, USA

    J Lappalainen, I Petrakis, J H Krystal & J Gelernter

  3. Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA

    H R Kranzler

  4. Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, USA

    G Page

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Lappalainen, J., Kranzler, H., Petrakis, I. et al. Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus. Mol Psychiatry 9, 312–319 (2004). https://doi.org/10.1038/sj.mp.4001429

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