Autosomal linkage analysis for the level of response to alcohol.
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 component 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 chromosome 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.
Schuckit
Marc A
MA
Department of Genetics and Neurology, the Carolina Center for Genome Sciences, Chapel Hill, NC, USA. mschuckit@ucsd.edu
Wilhelmsen
Kirk
K
Smith
Tom L
TL
Feiler
Heidi S
HS
Lind
Penelope
P
Lange
Leslie A
LA
Kalmijn
Jelger
J
D000293:Adolescent; D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology; D000437:Alcoholism / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005190:Family; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D004856:Postural Balance / Q000187:drug effects; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics; D012737:Sex Factors
D024681:Potassium Channels, Calcium-Activated; D000431:Ethanol