Using dimensional models of externalizing psychopathology to aid in gene identification.
BACKGROUND
Twin studies provide compelling evidence that alcohol and drug dependence, childhood conduct disorder, adult antisocial behavior, and disinhibitory personality traits share an underlying genetic liability that contributes to a spectrum of externalizing behaviors. However, this information has not been widely used in gene identification efforts, which have focused on specific disorders diagnosed using traditional psychiatric classification systems.


OBJECTIVE
To test the utility of using a multivariate externalizing phenotype in (1) linkage analyses and (2) association analyses to identify genes that contribute broadly to a spectrum of externalizing disorders.


METHODS
Data were analyzed from the Collaborative Study on the Genetics of Alcoholism. Linkage analyses were conducted using data from a genome-wide 10-cM microsatellite scan. Association analyses were conducted on 27 single-nucleotide polymorphisms genotyped across a candidate gene, the muscarinic acetylcholine receptor M2 gene (CHRM2).


METHODS
Six centers across the United States.


METHODS
Approximately 2300 individuals from 262 families.


METHODS
Lifetime symptom counts of alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder and novelty seeking, sensation seeking, and general externalizing component scores consisting of a composite of the previous 6 variables.


RESULTS
Principal component analyses indicated that the 6 individual variables loaded on a single externalizing factor. Linkage analyses using the resultant component scores identified a region on chromosome 7 consistent with a gene that broadly predisposes individuals to externalizing behavior. Association analyses of a candidate gene, CHRM2, previously of interest in the Collaborative Study on the Genetics of Alcoholism, suggest that it is involved in a general externalizing phenotype.


CONCLUSIONS
Broader conceptualizations of psychiatric disorders, such as studying a spectrum of externalizing psychopathology, may aid in identifying susceptibility genes and understanding the pathways through which genetic factors affect vulnerability for a variety of poor outcomes.
Dick
Danielle M
DM
Washington University, St Louis, Missouri, USA. ddick@vcu.edu
Aliev
Fazil
F
Wang
Jen C
JC
Grucza
Richard A
RA
Schuckit
Marc
M
Kuperman
Samuel
S
Kramer
John
J
Hinrichs
Anthony
A
Bertelsen
Sarah
S
Budde
John P
JP
Hesselbrock
Victor
V
Porjesz
Bernice
B
Edenberg
Howard J
HJ
Bierut
Laura Jean
LJ
Goate
Alison
A
D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D008962:Models, Theoretical; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D043585:Receptor, Muscarinic M2 / Q000235:genetics; D019966:Substance-Related Disorders / Q000235:genetics; D014481:United States
C487078:CHRM2 protein, human; D043585:Receptor, Muscarinic M2