Background: A previous genome-wide linkage study of alcohol dependence in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The KIAA0040 gene has been mapped to this region (1q24-q25). A recent genome-wide association study using SAGE (the Study of Addiction: Genetics and Environment) and COGA (Collaborative Study on the Genetics of Alcoholism) found five SNPs within the KIAA0040 gene significantly associated with alcohol dependence. A meta-analysis using data from these sources also found the KIAA0040 gene significantly associated with alcohol dependence. Methods: Using family data consisting of 1000 individuals with phenotypic data (762 with both phenotype and DNA), finer mapping of a 0.3 cM region that included the KIAA0040 gene and a flanking gene was undertaken using SNPs with minor allele frequency (MAF) ≥ 0.15 and pair-wise linkage disequilibrium (LD) of r2 < 0.8 using the HapMap CEU population. Results: Significant FBAT p-values were observed for six SNPs, four within the KIAA0040 gene (rs2269650, rs2861158, rs1008459, rs2272785) and two adjacent to KIAA0040 (rs10912899 and rs3753555). Five haplotype blocks of varying size were identified using HAPLOVIEW. Analysis using the haplotype-based test function of FBAT revealed one two-SNP block (rs1008459rs2272785) associated with alcohol dependence. This block showed a pattern of transmission in which one haplotype, CT, with a frequency of 0.577 was found to be over-transmitted to affected offspring (p = 0.017) while another haplotype, AG, with a frequency of 0.238 was found to be under-transmitted to affected offspring (p = 0.006). A three-SNP block (rs1008459rs2272785-rs375355) showed an overall significant association (p = 0.011) with alcohol dependence with the haplotype ACT over-transmitted to affected offspring (p = 0.016) and the haplotype GAG undertransmitted (p = 0.002). Conclusions: Family-based association analysis shows the KIAA0040 gene significantly associated with alcohol dependence. The potential importance of the KIAA0040 gene for AD risk is currently unknown. However, the present results support earlier findings from a genome-wide association study.
 Mokdad, A.H., Marks, J.S., Stroup, D.F. and Gerberding, J.L. (2004) Actual causes of death in the United States, 2000. JAMA, 291, 1238-1245.
 Harwood, H. (2000) Updating estimates of the economic costs of alcohol abuse in the United States: Estimates, update methods, and data. Report prepared by The Lewin Group for the National Institute on Alcohol Abuse and Alcoholism. Based on estimates, analyses, and data reported in Harwood H, Fountain D, and Livermore G. The economic costs of alcohol and drug abuse in the United States 1992. Report prepared for the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services. NIH Publication No. 98-4327. Rockville, MD: National Institutes of Health.
 Grant, B.F., Dawson, D.A., Stinson, F.S., Chou, S.P., Dufour, M.C. and Pickering, R.P. (2004) The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991-1992 and 2001-2002. Drug Alcohol Dependence, 74, 223-234.
 Hasin, D.S., Stinson, F.S., Ogburn, E. and Grant, B.F. (2007) Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on alcohol and related conditions. Archives of General Psychiatry, 64, 830-842.
 Kessler, R.C., Crum, R.M., Warner, L.A., Nelson, C.B., Schulenberg, J. and Anthony, J. (1997) Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorder in the national comorbidity survey. Archives of General Psychiatry, 54, 313-321.
 Caldwell, C.B. and Gottesman, I.I., (1991) Sex differences in the risk for alcoholism: A twin study. Behavior Genetics, 21, 563.
 Heath, A.C., Bucholz, K.K., Madden, P.A.F., Dinwiddie, S.H., Slutske, W.S., et al. (1997) Genetic and environmental contributions to alcohol dependence risk in a national twin sample: Consistency of findings in women and men. Psychological Medicine, 27, 1381-1396.
 Prescott, C.A., Aggen, S.H. and Kendler, K.S. (1999) Sex differences in the sources of genetic liability to alcohol abuse and dependence in a population based sample of US twins. Alcoholism: Clinical and Experimental Research, 23, 1136-1144.
 Kendler, K.S., Heath, A.C., Neale, M.C., Kessler, R.C. and Eaves, L.J., (1992) A population-based twin study of alcoholism in women. JAMA, 268, 1877-1882.
 Reich, T., Edenberg, H.J., Goate, A., Williams, J.T., Rice, J.P., et al. (1998) Genome-wide search for genes affecting the risk for alcohol dependence. American Journal of Medical Genetics Part B: Neuropsychiatr Genet, 81, 207-215.
 Edenberg, H.J., Dick, D.M., Xuei, X., Tian, H., Almasy, L., et al. (2004) Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. The American Journal of Human Genetics, 74, 705-714.
 Wang, K.S., Liu, X., Zhang, Q., Pan, Y., Aragam, N. and Zeng, M. (2011) A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence. Journal of Psychiatric Research, 45, 1419-1425. http://dx.doi.org/10.1016/j.jpsychires.2011.06.005
 Hill, S.Y., Shen, S., Zezza, N., Hoffman, E.K., Perlin, M. and Allan, W. (2004) A genome-wide search for alcoholism susceptibility genes. Am J Med Genet, Part B, 128B, 102-113. http://dx.doi.org/10.1002/ajmg.b.30013
 Hill, S.Y., Weeks, D.E., Jones, B.L., Zezza, N. and Stiffler, S. (2012) ASTN1 and Alcohol Dependence: Family-Based Association Analysis in Multiplex Alcohol Dependence Families. American Journal of Medical Genetics Part B, 159B, 445-455.
 Zuo, L., Gelernter, J., Zhang, C.K., Zhao, H., Lu, L., et al. (2012) Genome-Wide association study of alcohol dependence implicates KIAA0040 on Chromosome 1q. Neuropsychopharmacology, 37, 557-566.
 Helzer, J.E., Robins, L.N., McEvoy, L.T., Spitznagel, E.L., Stoltzman, R.K., et al. (1985) A comparison of clinical and diagnostic interview schedule diagnoses. Physician reexamination of lay-interviewed cases in the general population. Archives of General Psychiatry, 42, 657-666. http://dx.doi.org/10.1001/archpsyc.1985.01790300019003
 Feighner, J.P., Robins, E., Guze, S.B., Woodruff, R.A. Jr., Winokur, G. and Munoz, R. (1972) Diagnostic criteria for use in psychiatric research. Archives of General Psychiatry, 26, 57-63.
 Janca, A., Robins, L.N., Cottler, L.B. and Early, T.S. (1992) Clinical observation of assessment using the Composite International Diagnostic Interview (CIDI). An analysis of the CIDI field trials B wave II at the St. Louis site. The British Journal of Psychiatry, 160, 815-818.
 Cottler, L.B., Robins, L.N. and Helzer, J.E. (1989) The reliability of the CIDI-SAM: A comprehensive substance abuse interview. British Journal of Addiction, 84, 801-814. http://dx.doi.org/10.1111/j.1360-0443.1989.tb03060.x
 Tellegen, A., Lykken, D.T., Bouchard, T.J., Wilcox, K.J., Segal, N.L. and Rich, S. (1988) Personality similarity in twins reared apart and together. Journal of Personality and Social Psychology, 54, 1031-1039.
 O’Connell, J.R. and Weeks, D.E. (1998) PedCheck: A program for identifying genotype incompatibilities in linkage analysis. The American Journal of Human Genetics, 63, 259-266. http://dx.doi.org/10.1086/301904
 Lange, K., Cantor, R., Horvath, S., Perola, M., Sabatti, C., et al. (2001) Mendel version 4.0: A complete package for the exact genetic analysis of discrete traits in pedigree and population data sets. The American Journal of Human Genetics, 69, 504.
 Mukhopadhyay, N., Almasy, L., Schroeder, M., Mulvihill, W.P. and Weeks, D.E. (2005) Mega2: data-handling for facilitating genetic linkage and association analyses. Bioinformatics, 21, 2556-2557.
 Kong, X., Murphy, K., Raj, T., He, C., White P.S. and Matise, T.C. (2004) A combined linkage-physical map of the human genome. The American Journal of Human Genetics, 75, 1143-1148.
 Matise, T.C., Chen, F., Chen, W., De La Vega F.M., Hansen, M., et al. (2007) A second-generation combined linkage physical map of the human genome. Genome Research, 17, 1783-1786.
 Laird, N.M., Horvath, S. and Xu, X. (2000) Implementing a unified approach to family-based tests of association. Genetic Epidemiology, 19, S36-42.
 Rabinowitz, D. and Laird, N. (2000) A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information. Human Heredity, 504, 227-233.
 Spielman, R.S., McGinnis, R.E. and Ewens, W.J. (1993) Transmission test for linkage disequilibrium: The insulin gene region and insulin-dependent diabetes mellitus (IDDM). The American Journal of Human Genetics, 52, 506-516.
 Sinsheimer, J.S., Blangero, J. and Lange, K. (2000) Gamete-competition models. The American Journal of Human Genetics, 66, 1168-1172.
 Barrett, J.C., Fry, B., Maller, J. and Daly, M.J. (2005) HAPLOVIEW: Analysis and visualization of LD and haplo-type maps. Bioinformatics, 21, 263-265.
 Gabriel, S.B., Schaffner, S.F., Nguyen, H., Moore, J.M., Roy, J., et al. (2002) The structure of haplotype blocks in the human genome. Science, 296, 2225-2229.
 Horvath, S., Xu, X., Lake, S.L., Silverman, E.K., Weiss, S.T. and Laird, N.M. (2004) Family-based tests for associating haplotypes with general phenotype data: Application to asthma genetics. Genetic Epidemiology, 26, 61-69.
 Pruim, R.J., Welch, R.P., Sanna, S., Teslovich, T.M., Chines, P.S., et al. (2010) LocusZoom: Regional visualization of genome-wide association scan results. Bioinformatics, 26, 2336-2337.
 Peng, W., Wang, H.Y., Miyahara, Y., Peng, G. and Wang, R.-F. (2008) Tumor-associated galectin-3 modulats the function of tumor-reactive T cells. Cancer Research, 68, 7228-7236.
 Neidhardt, J., Fehr, S., Kutsche, M., Lohler, J. and Schachner, M. (2003) Tenascin-N: Characterization of a novel member of the tenascin family that mediates neurite repulsion from hippocampal explants. Molecular and Cellular Neuroscience, 23, 193-209.
 Hill, S.Y., Shen, S., Locke-Wellman J., Matthews, A.G. and McDermott, M. (2008) Psychopathology in offspring from multiplex alcohol dependence families: A prospective study during childhood and adolescence. Psychiatry Research, 160, 155-166.
 Hill, S.Y., Tessner, K.D., McDermott, M.D. (2011) Psychopathology in offspring from families of alcohol dependent female probands: A prospective study. Journal of Psychiatric Research, 45, 285-294.
 Hill, S.Y. (2010) Neural Plasticity, human genetics, and risk for alcohol dependence. In: Reilly, M.T. and Lovinger, D.M., Eds., Functional Plasticity and Genetic Variation, Academic Press, 53-94.
 Sahana, G., Guldbrandtsen, B., Janss, C. and Ott, J. (2010) Comparison of association mapping methods in a complex pedigree population. Genetic Epidemiology, 34, 455-462. http://dx.doi.org/10.1002/gepi.20499
 Risch, N. and Merikangas, K. (1996) The future of genetic studies of complex human diseases. Science, 273, 1516-1517.
 Maher, B. (2008) Personal genomes: The case of missing heritability. Nature, 456, 18-21.
 Mitchell, K.J. and Porteous, D.J. (2009) GWAS for psychiatric disease: Is the framework built on a solid foundation. Molecular Psychiatry, 14, 740-745.
 Suarez, B.K., Culverhouse, R., Jin, C.H. and Hinrichs, A. (2007) Linkage, case-control association, and family-based association tests for complex disorders. BMS Proceedings, 1, S43.