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An Autosomal Linkage Scan for Cannabis Use Disorders in the Nicotine Addiction Genetics Project
Arpana Agrawal, PhD;
Michele L. Pergadia, PhD;
Scott F. Saccone, PhD;
Michael T. Lynskey, PhD;
Jen C. Wang, PhD;
Nicholas G. Martin, PhD;
Dixie Statham, MPsychClin;
Anjali Henders, PhD;
Megan Campbell, BappSc;
Robertino Garcia, BS;
Ulla Broms, MHSc;
Richard D. Todd, PhD, MD;
Alison M. Goate, DPhil;
John Rice, PhD;
Jaakko Kaprio, MD, PhD;
Andrew C. Heath, DPhil;
Grant W. Montgomery, PhD;
Pamela A. F. Madden, PhD
Arch Gen Psychiatry. 2008;65(6):713-721.
Context 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.
Design 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  -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.
Author Affiliations: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri (Drs Agrawal, Pergadia, Saccone, Lynskey, Wang, Todd, Goate, Rice, Heath, and Madden and Mr Garcia); Queensland Institute of Medical Research, Brisbane, Australia (Drs Martin, Henders, and Montgomery and Mss Statham and Campbell); and Department of Public Health, University of Helsinki, Helsinki, Finland (Ms Broms and Dr Kaprio).
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