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Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4

Abstract

Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50–60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD=4.59, P=2.1 × 10−6, at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0–2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.

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Acknowledgements

We are grateful to the study participants and their families for their time and effort. We thank Aine Finnerty, Phil Gavigan, Craig Barton, John Cosgrove, Michael Crossan, Sara Dineen, Claire Killeen, Deirdre King, Siobhan McHugh, Amanda Mullan, Eileen Murphy, Brian O’Malley and Bernie Purcell for their roles in data collection and Ruth Barrington, Ros Moran and Carol Cronin for administrative support. F Anthony O’Neill of Queens University, Belfast NI, the Northern Ireland Blood Transfusion Service and the Irish Gardai provided assistance in obtaining control blood samples. John Myers assisted with data analysis, Indrani Ray and Cheryl Smith assisted with database management, Brandon Wormley assisted with genotyping, and Stacey Garnett, Jill Opalesky and Rebecca Ortiz provided administrative assistance at VCU. This work was funded by US National Institutes of Health grant R01-AA-11408 with administrative support from the Irish Health Research Board.

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Prescott, C., Sullivan, P., Kuo, PH. et al. Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4. Mol Psychiatry 11, 603–611 (2006). https://doi.org/10.1038/sj.mp.4001811

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Keywords

  • alcoholism
  • binge drinking
  • tolerance
  • family study
  • molecular genetics
  • genes

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