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Convergent Results From 2 Samples

George R. Uhl, MD, PhD; Tomas Drgon, PhD; Qing-Rong Liu, PhD; Catherine Johnson, MSc; Donna Walther, MSc; Tokutaro Komiyama, MD; Mutsuo Harano, MD; Yoshimoto Sekine, MD, PhD; Toshiya Inada, MD; Norio Ozaki, MD, PhD; Masaomi Iyo, MD, PhD; Nakao Iwata, MD, PhD; Mitsuhiko Yamada, MD; Ichiro Sora, MD, PhD; Chih-Ken Chen, MD, PhD; Hsing-Cheng Liu, MD, PhD; Hiroshi Ujike; Shih-Ku Lin, MD

Arch Gen Psychiatry. 2008;65(3):345-355.

Context  We can improve understanding of human methamphetamine dependence, and possibly our abilities to prevent and treat this devastating disorder, by identifying genes whose allelic variants predispose to methamphetamine dependence.

Objective  To find "methamphetamine dependence" genes identified by each of 2 genome-wide association (GWA) studies of independent samples of methamphetamine-dependent individuals and matched controls.

Design  Replicated GWA results in each of 2 case-control studies.

Setting  Japan and Taiwan.

Participants  Individuals with methamphetamine dependence and matched control subjects free from psychiatric, substance abuse, or substance dependence diagnoses (N = 580).

Main Outcome Measures  "Methamphetamine dependence" genes that were reproducibly identified by clusters of nominally positive single-nucleotide polymorphisms (SNPs) in both samples in ways that were unlikely to represent chance observations, based on Monte Carlo simulations that corrected for multiple comparisons, and subsets of "methamphetamine dependence" genes that were also identified by GWA studies of dependence on other addictive substances, success in quitting smoking, and memory.

Results  Genes identified by clustered nominally positive SNPs from both samples were unlikely to represent chance observations (Monte Carlo P < .00001). Variants in these "methamphetamine dependence" genes are likely to alter cell adhesion, enzymatic functions, transcription, cell structure, and DNA, RNA, and/or protein handling or modification. Cell adhesion genes CSMD1 and CDH13 displayed the largest numbers of clustered nominally positive SNPs. "Methamphetamine dependence" genes overlapped, to extents much greater than chance, with genes identified in GWA studies of dependence on other addictive substances, success in quitting smoking, and memory (Monte Carlo P range < .04 to < .00001).

Conclusion  These data support polygenic contributions to methamphetamine dependence from genes that include those whose variants contribute to dependence on several addictive substances, success in quitting smoking, and mnemonic processes.

Author Affiliations: Molecular Neurobiology Branch, National Institutes of Health Intramural Program, Department of Health and Human Services, Baltimore, Maryland (Drs Uhl, Drgon, and Q-R. Liu and Mss Johnson and Walther); Division of Psychiatry, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Tokyo, Japan (Dr Komiyama); Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Japan (Dr Harano); Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan (Dr Sekine); Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan (Drs Inada and Ozaki); Department of Psychiatry, Teikyo University School of Medicine, Chiba Medical Center (Dr Inada), and Department of Psychiatry, Graduate School of Medicine, Chiba University (Dr Iyo), Chiba, Japan; Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan (Dr Iwata); Department of Psychiatry, Showa University Northern Yokohama Hospital, Yokohama, Japan (Dr Yamada); Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan (Dr Sora); Japanese Genetics Initiative on Drug Abuse (Drs Komiyama, Harano, Sekine, Inada, Ozaki, Iyo, Iwata, Yamada, Sora and Ujike); Department of Psychiatry, Chang Gung Memorial Hospital, Keelung, Taiwan (Dr Chen); Department of Psychiatry, Taipei City Hospital, and Taipei City Psychiatric Center, Taipei, Taiwan, Republic of China (Drs H-C. Liu and Lin); Department of Neuropsychiatry, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan (Dr Ujike).