An autosomal linkage scan for cannabis use disorders in the nicotine addiction genetics project.
BACKGROUND
Despite accumulating evidence that there is a genetic basis for cannabis use disorders (ie, abuse and dependence), few studies have identified genomic regions that may harbor biological risk and protective factors.


OBJECTIVE
To conduct autosomal linkage analyses that identify genomic regions that may harbor genes conferring a vulnerability to cannabis use disorders.


METHODS
In 289 Australian families who participated in the Nicotine Addiction Genetics Project, 423 autosomal markers were genotyped. Families were ascertained for heavy cigarette smoking. Linkage was conducted for DSM-IV cannabis dependence and for a novel factor score representing problems with cannabis use, including occurrence of 3 of 4 abuse criteria (excluding legal problems) and 6 DSM-IV dependence criteria.


RESULTS
A maximum logarithm of odds (LOD) of 3.36 was noted for the cannabis problems factor score on chromosome arm 1p. An LOD of 2.2 was noted on chromosome 4 in the region of the gamma-aminobutyric acid type A gene cluster, including GABRA2, which has been implicated in drug use disorders. For DSM-IV cannabis dependence, a modest LOD score on chromosome 6 (1.42) near cannabinoid receptor 1 (CNR1) was identified. In addition, support for an elevation on chromosome 3, identified in prior independent studies, was noted for the factor score and cannabis dependence (LOD, 1.4).


CONCLUSIONS
Genes such as ELTD1 on chromosome 1, in addition to genes on chromosomes 4 (eg, GABRA2) and 6 (eg, CNR1), may be associated with the genetic risk for cannabis use disorders. We introduce a novel quantitative phenotype, a cannabis problems factor score composed of DSM-IV abuse and dependence criteria, that may be useful for future linkage and association studies.
Agrawal
Arpana
A
Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8134, St Louis, MO 63110, USA. arpana@wustl.edu
Pergadia
Michele L
ML
Saccone
Scott F
SF
Lynskey
Michael T
MT
Wang
Jen C
JC
Martin
Nicholas G
NG
Statham
Dixie
D
Henders
Anjali
A
Campbell
Megan
M
Garcia
Robertino
R
Broms
Ulla
U
Todd
Richard D
RD
Goate
Alison M
AM
Rice
John
J
Kaprio
Jaakko
J
Heath
Andrew C
AC
Montgomery
Grant W
GW
Madden
Pamela A F
PA
D000328:Adult; D001315:Australia; D015816:Cell Adhesion Molecules, Neuronal; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004200:Diseases in Twins / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008297:Male; D002189:Marijuana Abuse / Q000235:genetics*; D008875:Middle Aged; D009479:Neuropeptides; D010641:Phenotype; D000091363:Protocadherins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics; D014029:Tobacco Use Disorder / Q000235:genetics*
C428324:ADGRL4 protein, human; D015816:Cell Adhesion Molecules, Neuronal; C484841:GABRA2 protein, human; D005819:Genetic Markers; D009479:Neuropeptides; C484820:PCDHA4 protein, human; D000091363:Protocadherins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A