Genome-wide association study identifies a novel locus for cannabis dependence.

paper Primary Public

Authors: Agrawal, A; Chou, Y-L; Carey, C E; Baranger, D A A; Zhang, B; Sherva, R; Wetherill, L; Kapoor, M; Wang, J-C; Bertelsen, S; Anokhin, A P; Hesselbrock, V; Kramer, J; Lynskey, M T; Meyers, J L; Nurnberger, J I; Rice, J P; Tischfield, J; Bierut, L J; Degenhardt, L; Farrer, L A; Gelernter, J; Hariri, A R; Heath, A C; Kranzler, H R; Madden, P A F; Martin, N G; Montgomery, G W; Porjesz, B; Wang, T; Whitfield, J B; Edenberg, H J; Foroud, T; Goate, A M; Bogdan, R; Nelson, E C
Year: 2018
Journal: Molecular psychiatry
PMID: 29112194
DOI: 10.1038/mp.2017.200
PMCID: PMC5938138

#	Section	Preview
20	RESULTS — GWAS results — Genomic and Epigenomic Annotation	There was also evidence that rs1409568 altered the binding motif for several transcription factors…
21	RESULTS — GWAS results — Genomic and Epigenomic Annotation	We identified 26 CpG probes that corresponded to genes with transcription start sites (TSS) within 1…
22	RESULTS — GWAS results — Sensitivity to definition of controls	The chromosome 10 SNPs represented a single signal (Supplemental Figure S6), so follow-up analyses…
23	RESULTS — GWAS results — Comorbidity with other substance use disorders	Only nicotine dependence was associated with rs1409568, and in CATS alone (p = .003) – adding…
24	RESULTS — GWAS results — Comorbidity with other substance use disorders — Genotype and brain volumetric variation	In the DNS, 51% of the sample reported lifetime cannabis use, with 12% (n=52), 15% (n=66), 8.8%…
25	RESULTS — GWAS results — Comorbidity with other substance use disorders — Genotype and brain volumetric variation	associated with cannabis use (i.e., left hippocampus and bilateral amygdala and ventral striatum)…
26	DISCUSSION	This study identified a genomewide significant locus on chromosome 10 for cannabis dependence…
27	DISCUSSION	The genomewide significant chromosome 10 SNPs represent a single LD signal, and are located in a…
28	DISCUSSION	One genomewide significant SNP, rs1409568, appears to be located within an active enhancer (52).…
29	DISCUSSION	Importantly, rs1409568 is predicted to bear active enhancer marks in several brain-derived tissues…
30	DISCUSSION	There was also nominal evidence that rs1409568 genotype was associated with changes in CpG…
31	DISCUSSION	In an independent sample, the C allele of rs1409568 was also associated with a modest increase in…
32	DISCUSSION	Cannabis use itself was associated with a modest increase (3.18%) in left (but not right)…
33	DISCUSSION	The minor allele of rs1409568, which was more common in cannabis dependent cases in the…
34	DISCUSSION	It is also noteworthy that the current study did not replicate previously noted associations for…
35	DISCUSSION	While no single SNP was genomewide significant for the count of DSM criteria, gene-level testing…
36	DISCUSSION	Some limitations are noteworthy. First, despite aggregating across several large datasets, our…
37	DISCUSSION	We identified a new genomewide significant locus on chromosome 10 that was associated with…
38	DISCUSSION	into cannabis involvement has lagged behind that of other drugs, despite the pressing public health…

Name	Type
1000 Genomes Project	cohort
AA participants	cohort
addiction	phenotype
addiction phenotypes	phenotype
African American	cohort
AL15778.1 local	gene
AL356865.1 local	gene
AL356865.2 local	gene
alcohol dependence	phenotype
amygdala	anatomy
amygdala volume	phenotype
angular gyrus	anatomy
ASW	cohort
azoospermia local	phenotype
behavioral phenotypes	phenotype
brain	anatomy
brain-derived tissues local	anatomy
CACUL1 local	gene
Cannabis abuse (DSM-IV) local	phenotype
cannabis dependence	phenotype
cannabis dependence criterion count local	phenotype
cannabis dependence diagnosis local	phenotype
Cannabis dependence (DSM-IV) local	phenotype
cannabis dependence symptom counts local	phenotype
cannabis use	phenotype
cannabis use disorder	phenotype
Cats	cohort
cerebellum	anatomy
CEU	cohort
cg23182539 local	variant
chr10 locus local	variant
chromosome 10 SNPs local	variant
Chronic cannabis use local	drug
cigarettes	phenotype
cingulate cortex	anatomy
CNR2	gene
COGA-cc local	cohort
COGA-ccGWAS local	cohort
COGA-f local	cohort
COGA-fGWAS local	cohort
Collaborative Study on the Genetics of Alcoholism (COGA)	cohort
college students	cohort
Common Mind Consortium	cohort
Comorbidity and Trauma Study local	cohort
control	cohort
CpG methylation of TIAL1 local	phenotype
Crohn’s disease	phenotype
CSMD1	gene
CT local	cohort
Digit-span performance local	phenotype
discovery analysis local	cohort
dlPFC	anatomy
DNase1 hypersensitivity site local	drug
DNS sample local	cohort
dorsolateral prefrontal cortex	anatomy
DSM-IV alcohol dependence	phenotype
DSM-IV cannabis dependence	phenotype
DSM-IV cannabis dependence criterion counts local	phenotype
Duke Neurogenetics Study	cohort
EA participants	cohort
endocannabinoid system	drug
enhancer	drug
ENIGMA meta-analysis local	cohort
European ancestry	cohort
European population	cohort
Five European descent cohorts local	cohort
frontal cortex	anatomy
genetic liability	phenotype
gray matter	anatomy
GTEx	cohort
H3K27ac	drug
H3K27ac marks local	drug
H3K4me1	drug
heavy cannabis use	phenotype
Higher socioeconomic status	phenotype
Hippocampal volume	anatomy
hippocampus	anatomy
HOXD8 local	gene
Illumina platform	drug
Independent EA college student cohort local	cohort
inferior temporal lobe local	anatomy
LDHAP5 local	gene
male fertility local	phenotype
male reproductive health local	phenotype
MEI1 local	gene
meta-analysis	cohort
middle hippocampus local	anatomy
NANOS1 local	gene
nicotine dependence	phenotype
Occasional cannabis use local	drug
opioid dependence	phenotype
OZALC	cohort
OZALC+ local	cohort
POU4F1	gene
POU4F3	gene
Pou6f2	gene
PRLHR local	gene
problem cannabis use	phenotype
psychiatric disorders	phenotype
Regional gray matter volume local	phenotype
replication analysis local	cohort
right hippocampal volume local	phenotype
risk factor	phenotype
RP11-215A21.1 local	gene
RP11-215A21.2 local	gene
RP11-498J9.2 local	gene
rs1409568	variant
rs150525973 local	variant
rs2287641 local	variant
rs7098706 local	variant
rs77300175 local	variant
rs77378271	variant
SAGE	cohort
Sherva et al local	cohort
Sherva et al top EA locus local	variant
SLC25A18P1 local	gene
sperm concentration local	phenotype
sperm count local	phenotype
striatum	anatomy
Stringer et al top 10 signals local	variant
study cohort	cohort
Study of Addictions: Genes and Environment local	cohort
substance use	phenotype
substantia nigra	anatomy
symptom count	phenotype
TIAL1 local	gene
TOMM22P5 local	gene
Total intracranial volume (ICV) local	phenotype
TT	cohort
U3 local	gene
United States	cohort
VAX1 local	gene
ventral striatum	anatomy
Yale-Penn	cohort
Yale-Penn sample	cohort
Yale-Penn study	cohort

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