Autosomal Linkage Analysis for the Level of Response to Alcohol Marc A. Schuckit, Kirk Wilhelmsen, Tom L. Smith, Heidi S. Feiler, Penelope Lind, Leslie A. Lange, and Jelger Kalmijn Background: The level of response (LR) to alcohol is a genetically-influenced phenotype related to the alcoholism risk. Usually measured by evaluating psychological and physiological changes that follow the administration of alcohol, the heritability of LR is estimated to be between 0.4 and 0.6, and efforts are being made to find genes related to this phenotype. This paper presents data from a family-based genome with linkage analysis focusing on alcohol challenge determinants of LR. Methods: The subjects were 18-to-29-year-old sibling pairs with at least one parent who was alcohol- dependent and who had experience with alcohol but were not yet alcohol-dependent themselves. Both members of the sibling pairs were given oral alcohol challenges (0.75-0.90 ml/kg of ethanol for females and males, respectively), with LR established using the Subjective High Assessment Scale (SHAS) and changes in body sway (BS) repeatedly over a 3.5-hr. period. Blood samples from siblings and at least one parent were genotyped using 811 microsatellite markers, with results evaluated using several related variance compo- nent approaches as implemented in SOLAR for continuous traits. In addition, association was tested using single nucleotide polymorphisms (SNPs) within the KCNMA1, HTR7 and SLC18A2 genes that may relate to a finding on chromosome 10. Results: Data were generated from 238 sib-pairs representing 365 individuals (41.6% were males) from 165 families. The most consistent results across methods and samples were observed for SHAS on chro- mosome 10 between 120 and 140 cM (with a maximum LOD score of 2.6 at 122 cM), and a second region of possible interest at 173 cM (LOD = 1.2). Statistical analysis with the KCNMA1, HTR7 and SLC18A2 genes, which lie in the support region of interest revealed no evidence for association after correction for multiple comparisons. Conclusions: These evaluations from the largest known alcohol challenge-based genetic study to date highlight the potential importance of genes on chromosome 10 as possible contributors to the low LR to alcohol as a risk factor for alcoholism. Key Words: Alcoholism, Alcohol Challenge, Linkage Analysis, KCNMA1 A low level of response (LR) to alcohol has been estab- lished as one of several genetically-influenced pheno- types related to the risk for alcoholism (Erblich and Ear- leywine, 1999; Pollock, 1992; Schuckit, 2002). Measured either by alcohol challenges or the self-report of the num- ber of drinks needed for various effects, in most studies evidence of a less intense response to this substance corre- lates with a family history (FH) of alcohol use disorders (AUDs), and predicts a high risk for alcohol problems (Heath et al., 1999; Schuckit and Smith, 2000; Volavka et al., 1996). Aspects of LR have been shown to be genetically influenced in animal models and in humans, with twin and family studies indicating heritabilities of 0.4 to 0.6 (Baldwin et al., 1991; Heath et al., 1999; Hu et al., 2005; Schuckit et al., 2005). Both association and genome-wide chromosome segre- gation (linkage) analyses have been used to search for genes potentially related to LR. However, relatively few of the many genes that could reasonably be analyzed have been directly surveyed for polymorphisms that affect the LR to alcohol (Schuckit et al., 2004a). Recent association studies using alcohol challenges in humans and animals have highlighted the potential importance of the GABA A6 gene on chromosome 5 as a potential contributor to the low LR and enhanced AUD risk (Barr et al., 2003; Hu et al., 2005; Schuckit et al., 1999). Such investigations have also supported the potential relationship between several poly- morphisms of the serotonin transporter (SERT) gene on chromosome 17 and alcohol intake, as well as alcohol- related problems (Ernouf et al., 1993; Hu et al., 2005; Schuckit et al., 1999). As recently reviewed (Schuckit et al., From the Departments of Genetics and Neurology, the Carolina Center for Genome Sciences (KW, PL), and the Bowles Center for Alcohol Studies (MAS, TLS, HSF, LAL, JK), Chapel Hill, NC. Received for publication February 10, 2005; accepted August 8, 2005. This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco; the Veterans Affairs Research Service; NIAAA Grant No. 05526, and a grant from the CompassPoint Addiction Foundation. Reprint requests: Marc A. Schuckit, Department of Psychiatry (116A), University of California, San Diego and the VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161-2002; Fax: (858) 552- 7424; E-mail: mschuckit@ucsd.edu Copyright © 2005 by the Research Society on Alcoholism. DOI: 10.1097/01.alc.0000187598.82921.27 0145-6008/05/29011-1976$03.00/0 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 29, No. 11 November 2005 1976 Alcohol Clin Exp Res, Vol 29, No 11, 2005: pp 1976–1982