TY - JOUR
T1 - A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans
AU - Cheng, Zhongshan
AU - Phokaew, Chureerat
AU - Chou, Yi Ling
AU - Lai, Dongbing
AU - Meyers, Jacquelyn L.
AU - Agrawal, Arpana
AU - Farrer, Lindsay A.
AU - Kranzler, Henry R.
AU - Gelernter, Joel
N1 - Funding Information:
This study was supported by National Institutes of Health grants R01 DA12690, R01 AA11330, R01 AA017535, and the VA Connecticut Healthcare Center and Philadelphia VA MIRECCs. We appreciate the work in recruitment and assessment by James Poling, PhD, at Yale University School of Medicine and the APT Foundation; Roger Weiss, MD, at McLean Hospital; by Kathleen Brady, MD/PhD, and Raymond Anton, MD, at the Medical University of South Carolina, and David Oslin, MD, at the University of Pennsylvania. Genotyping services for a part of our GWAS were provided by the Center for Inherited Disease Research and Yale University (Center for Genome Analysis), which is fully funded by Federal contract N01-HG-65403 from the NIH to The Johns Hopkins University. We thank Ann Marie Lacobelle, MS, and Christa Robinson, BS, who provided technical assistance. We thank Yaira Nunez and Michelle Slivinsky, who led the QC effort for the Semi-Structured Assessment for Drug Dependence and Alcoholism interviews, and phenotyping for the study sample. We thank John Farrell, PhD, Section of Biomedical Genetics, Boston University School of Medicine, who provided database management assistance. We also thank Drs Hang Zhou, Renato Polimanti, and Daniel Levey for their constructive suggestions on the statistical analysis. COGA: The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut; includes 11 different centers: University of Connecticut (V. Hesselbrock), Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud, Y. Liu), University of Iowa (S. Kuperman, J. Kramer), SUNY Downstate (B. Porjesz), Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A. Agrawal), University of California at San Diego (M. Schuckit), Rutgers University (J. Tischfield, A. Brooks), Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA (L. Almasy), Virginia Commonwealth University (D. Dick), Icahn School of Medicine at Mount Sinai (A. Goate), and Howard University (R. Taylor). Other COGA collaborators include the following: L. Bauer (University of Connecticut); J. McClintick, L. Wetherill, X. Xuei, D. Lai, S. O’Connor, M. Plawecki, S. Lourens (Indiana University); G. Chan (University of Iowa; University of Connecticut); J. Meyers, D. Chorlian, C. Kamarajan, A. Pandey, J. Zhang (SUNY Downstate); J.-C. Wang, M. Kapoor, S. Bertelsen (Icahn School of Medicine at Mount Sinai); A. Anokhin, V. McCutcheon, S. Saccone (Washington University); J. Salvatore, F. Aliev, B. Cho (Virginia Commonwealth University); and Mark Kos (University of Texas Rio Grande Valley). A. Parsian and H. Chen are the NIAAA Staff Collaborators. COGA investigators continue to be inspired by memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Arpana Agrawal also acknowledges support from K02DA032573.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Cannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10−10), rs74722579 (P = 2.81 × 10−9), and rs1938228 (P = 1.57 × 10−8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs’ association signals were increased (meta-P-values 1.32 × 10−10 and 2.60 × 10−9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.
AB - Cannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10−10), rs74722579 (P = 2.81 × 10−9), and rs1938228 (P = 1.57 × 10−8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs’ association signals were increased (meta-P-values 1.32 × 10−10 and 2.60 × 10−9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.
UR - http://www.scopus.com/inward/record.url?scp=85075151765&partnerID=8YFLogxK
U2 - 10.1038/s41398-019-0639-7
DO - 10.1038/s41398-019-0639-7
M3 - Article
C2 - 31740666
AN - SCOPUS:85075151765
SN - 2158-3188
VL - 9
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 309
ER -