0145-6008/00/2407-0933$03.00/0 ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH zyxwvutsrqpo Vol. 24, No. zy I July 2000 Alcoholism Susceptibility Loci: Confirmation Studies in a Replicate Sample and Further Mapping zy Tatiana Foroud, Howard J. Edenberg, Alison Goate, John Rice, Leah Flury, Daniel L. Koller, Laura J. Bierut, P. Michael Conneally, John I. Nurnberger, Kathleen K. Bucholz, Ting-Kai Li, Victor Hesselbrock, Raymond Crowe, Marc Schuckit, Bernice Porjesz, Henri Begleiter, and Theodore Reich Background There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. Methods: AdditionaLgenotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-111-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets. Key Words: Alcoholism, Nonparametric Linkage Analysis, Sibling Pair, Susceptibility Genes. LCOHOL DEPENDENCE IS a common, familial dis- A order that is a leading cause of morbidity and prema- ture death (Caces et al., 1995; Campbell et al., 1996; De- Bakery et al., 1995). Family studies have documented a 3- to 5-fold increased risk for alcoholism among siblings and other first-degree relatives of affected individuals (Cotton, 1979; Reich et al., 1998). The risk for alcoholism is in- creased even if the offspring of an alcoholic is adopted away from the home (Cloninger et al., 1981; Goodwin et al., 1973). In addition, twin studies have identified a significant zyxwvu From Indiana University School of Medicine (T.F., H.J.E., L.F., D.L.K., P.M. C., J.I.N., T-K. Li), Indianapolis, Indiana; Washington University School of Medicine (A.G., J.R., L.J.B., K K B . , T.R.), St. Louis, Missouri; University of Connecticut School of Medicine (V. H.), Farmington, Connect- icut; University of Iowa School of Medicine (R.C.),Iowa City, Iowa; UCSD School of Medicine (M.S.), La Jolla, California; and zyxwvuts SUNY Health Science Center at Brooklyn (B.P., H.B), Brooklyn, New York. Received for publication January 12, 2000; accepted April 18, 2000. The Collaborative Study on the Genetics of Alcoholism (COGA) is sup- ported by Grant UIOAA08403from the National Institute on Alcohol Abuse and Alcoholism ( NW), National Institutes of Health. Preparation of this manuscript also was supported by NIAAA Grant KO2A.400285-01 (T.F.). Reprint requests: Tatiana Foroud, Ph.D., Department of Medical and Molec- ular Genetics, Indiana University School of Medicine, 975 U? Walnut St. IB-155, Indianapolis, IN 46202; Far: 31 7-274-2387 E-mail: tfooud@iupui.edu Copyright zyxwvutsrqpon 0 2000 by the Research Society on Alcoholism. Alcohol Clin Exp Res, Vol24, No I, 2000 pp 933-945 genetic component to alcoholism risk, with estimates of heritability ranging from 50% to 60% (Heath et al., 1997). Based on these findings, it is likely that alcoholism is a complex genetic disorder that results from the action of multiple, possibly interacting, genes as well as environmen- tal influences. Initial efforts to identify the genetic loci that underlie alco- holism susceptibility in human subjects relied on the evalua- tion of candidate genes. Studies of several candidate genes, notably the dopamine D2 receptor (DRD2) gene on chromo- some 11 (Amadeo et al., 1993; Arinami et al., 1993; Blum et al., 1990,1991;Bolos et al., 1991; Chen et al., 1996a;Comings et al., 1991; Cook et al., 1992; Edenberg et al., 1998a; Gelert- ner et al., 1991; Goldman et al., 1992, 1993, 1997; Lu et al., 1996; Neiswanger et al., 1995; Noble et al., 1994; O’Hara et al., 1993;Parsian et al., 1991; Sander et al., 1995;Schwabet al., 1991; Suarez et al., 1994b; Turner et al., 1992) and the sero- tonin transporter gene zyxw (HTT) on chromosome 17 (Edenberg et al., 1998b; Sander et al., 1997) have resulted in inconsistent findings, which suggests it is unlikely that either plays a major role in alcoholism susceptibility. The only consistently repli- cated findings are those that involve the protective effects of certain functional polymorphisms of the alcohol metabolizing enzymes alcohol dehydrogenase (ADH) and the mitochon- drial aldehyde dehydrogenase (Chen et al., 1996b; Higuchi et z 933