The Investigation into CYP2E1 in Relation to the Levelof Response to Alcohol Through a Combination of Linkage and Association Analysis2
Amy Webb, Penelope A. Lind, Jelger Kalmijn, Heidi S. Feiler, Tom L. Smith,Marc A. Schuckit, and Kirk Wilhelmsen
A low level of response to alcohol during an individual’s early experience withalcohol is associated with an increase risk of alcoholism. A family-based genome-wide linkageanalysis using sibling pairs that underwent an alcohol challenge where the level of response toalcohol was measured with the Subjective High Assessment Scale (SHAS) implicated the 10q ter-minal (10qter) region.
, a gene known for its involvement with ethanol metabolism, mapsto this region.
Variance component multipoint linkage analysis was performed on a combined mapof single-nucleotide polymorphism (SNP) and microsatellite data. To account for the heterogene-ity evident in the dataset, a calculation assuming locus heterogeneity was made using the Hetero-geneity Log of Odds (HLOD) score. Association between SNP marker allele counts and copynumber and SHAS scores were evaluated using a logistic regression model.
Linkage analysis detected signiﬁcant linkage to
which was diminishedbecause of apparent locus heterogeneity traced to a single family with extreme phenotypes. Inretrospect, circumstances recorded during testing for this family suggest that their phenotype dataare likely to be unreliable. Signiﬁcant allelic associations were detected for several
poly-morphisms and the SHAS score. DNA sequencing from families that contributed the greatest evi-dence for linkage did not detect any changes directly affecting the primary amino acid sequence.With the removal of a single family, combined evidence from microsatellites and SNPs offerssigniﬁcant linkage between the level of response to alcohol and the region on the end of chromo-some 10.
Combined linkage and association indicate that sequence changes in or near
affect the level of response to alcohol providing a predictor of risk of alcoholism. Theabsence of coding sequence changes indicates that regulatory sequences are responsible. Implicat-ing
in the level of response to alcohol allows inferences to be made about how the brainperceives alcohol.
Level of Response to Alcohol, Linkage Analysis, Association Analysis, CombinedLinkage and Association, CYP2E1, Locus Heterogeneity.
HILE A NUMBER of phenotypic factors can affectthe risk of alcoholism, one of the most studied end-ophenotypes is an individual’s level of response to alcoholduring their early experience with alcohol (Heath et al., 1999).The level of response to alcohol can be reliably measured withthe Subjective High Assessment Scale (SHAS) during an alco-hol challenge or by the Self-Rating of the Effects of Alcohol,which uses recall to establish the number of drinks requiredto reach an effect. Children of alcoholics have a greater riskof alcoholism when they have a lower level of response(Pollock, 1992; Schuckit and Smith, 1996; Schuckit et al.,2000). A low level of response established early in an indivi-dual’s drinking career can lead to higher future drinking levels(Ehlers et al., 1999; Heath et al., 1999; Volavka et al., 1996).Populations at historically higher risk of alcoholism, such asNative American or Korean, need to consume larger amountsof alcohol to become intoxicated (Garcia-Andrade et al.,1997; Luczak et al., 2002; Wall et al., 1999) compared tothose with lower risk (Monteiro et al., 1991) who exhibit amore intense level of response to alcohol. Several studies have
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Journal Name Manuscript No.
Author Received: No. of pages: 9 PE: Amal
From the Department of Biomedical Engineering (AW), Univer-sity of North Carolina at Chapel Hill, Chapel Hill, North Carolina;Genetic Epidemiology (PAL), Queensland Institute of Medical Research, Brisbane, Queensland, Australia; Department of Psychiatry(JK, TLS, MAS), University of California, San Diego, and the Vet-erans Affairs San Diego Healthcare System, San Diego, California;Life Sciences Division (HSF), Lawrence Berkeley National Labora-tory, Berkeley, California; and Department of Genetics and Neurology(KW), University of North Carolina at Chapel Hill, Chapel Hill,North Carolina.Received for publication November 12, 2009; accepted June 21, 2010.Reprint requests: Kirk C. Wilhelmsen, MD,PhD, UNC-CH Department of Neurology and Genetics, 120 Mason Farm Road,Campus Box #7264, Chapel Hill, North Carolina 27599-7264; Tel.:(919) 966-1373; Fax: (919) 966-3630; E-mail: email@example.comCopyright
2010 by the Research Society on Alcoholism.
Alcoholism: Clinical and Experimental Research
Vol. 35, No. 1January 2011
Alcohol Clin Exp Res,
Vol 35, No 1, 2011: pp 1–9 1