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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References
Foroud T, Edenberg HJ, Goate A, Rice J, Flury L, Koller DL et al. Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping. Alcohol Clin Exp Res 2000; 24: 933–945.
Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, Van Eerdewegh P et al. Genome-wide search for genes affecting the risk for alcohol dependence. Am J Med Genet 1998; 81: 207–215.
Dick DM, Nurnberger J, Edenberg HJ, Goate A, Crowe R, Rice J et al. Suggestive linkage on chromosome 1 for a quantitative alcohol-related phenotype. Alcohol Clin Exp Res 2002; 26: 1453–1460.
Schuckit MA, Edenberg HJ, Kalmijn J, Flury L, Smith TL, Reich T et al. A genome-wide search for genes that relate to a low level of response to alcohol. Alcohol Clin Exp Res 2001; 25: 323–329.
Nurnberger Jr JI, Foroud T, Flury L, Su J, Meyer ET, Hu K et al. Evidence for a locus on chromosome 1 that influences vulnerability to alcoholism and affective disorder. Am J Psychiatry 2001; 158: 718–724.
Kendler KS, Heath AC, Neale MC, Kessler RC, Eaves LJ . Alcoholism and major depression in women – a twin study of the causes of comorbidity. Arch Gen Psychiatry 1993; 50: 690–698.
Merikangas KR, Gelernter CS . Comorbidity for alcoholism and depression. Psychiatr Clin North Am 1990; 13: 613–632.
Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC . Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry 1997; 54: 313–321.
Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990; 264: 2511–2518.
Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.
Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.
Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337–348.
Abecasis GR, Noguchi E, Heinzmann A, Traherne JA, Bhattacharyya S, Leaves NI et al. Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 2001; 68: 191–197.
Varilo T, Paunio T, Parker A, Perola M, Meyer J, Terwilliger JD et al. The interval of linkage disequilibrium (LD) detected with microsatellite and SNP markers in chromosomes of Finnish populations with different histories. Hum Mol Genet 2003; 12: 51–59.
Spitzer RL, Williams JB, Gibbon M, First MB . The Structured Clinical Interview for DSM-III-R (SCID). I: history, rationale, and description. Arch Gen Psychiatry 1992; 49: 624–629.
Endicott J, Spitzer RL . A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978; 35: 837–844.
Sobel E, Lange K . Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 1996; 58: 1323–1337.
Abecasis GR, Cookson WO . GOLD – graphical overview of linkage disequilibrium. Bioinformatics 2000; 16: 182–183.
Sham PC, Curtis D . An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet 1995; 59: 323–336.
Dudbridge F, Koeleman BP, Todd JA, Clayton DG . Unbiased application of the transmission/disequilibrium test to multilocus haplotypes. Am J Hum Genet 2000; 66: 2009–2012.
Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B et al. A high-resolution recombination map of the human genome Nat. Genetics 2002; 31: 241–247.
Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 1997; 15: 236–246.
Hoyng CB, Poppelaars F, van de Pol TJ, Kremer H, Pinckers AJ, Deutman AF et al. Genetic fine mapping of the gene for recessive Stargardt disease. Hum Genet 1996; 98: 500–504.
Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29: 223–228.
Kaplan DE, Gayan J, Ahn J, Won TW, Pauls D, Olson RK et al. Evidence for linkage and association with reading disability on 6p21.3-22 Am. J Hum Genet 2002; 70: 1287–1298.
Purcell S, Cherny SS, Sham PC . Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.
Shen YC, Fan JH, Edenberg HJ, Li TK, Cui YH, Wang YF et al. Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism. Alcohol Clin Exp Res 1997; 21: 1272–1277.
Lappalainen J, Kranzler HR, Malison R, Price LH, Van Dyck C, Rosenheck RA et al. A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Arch Gen Psychiatry 2002; 59: 825–831.
Porjesz B, Almasy L, Edenberg HJ, Wang K, Chorlian DB, Foroud T et al. Linkage disequilibrium between the beta frequency of the human EEG and a GABAA receptor gene locus. Proc Natl Acad Sci USA 2002; 99: 3729–3733.
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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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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DOI: https://doi.org/10.1038/sj.mp.4001429
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