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GWAS Identifies Loci Linked to Cannabis Dependence

NEW YORK (GenomeWeb) – A condition called cannabis dependence may share some genetic ties to psychiatric conditions such as major depressive disorder or schizophrenia, according to a genome-wide association study published online today in JAMA Psychiatry.

A Yale University-led team did a GWAS involving nearly 15,000 individuals recruited from the community and substance abuse centers who had a range of cannabis dependence symptoms as defined in the DSM-IV. The search led to three loci with apparent cannabis dependence associations as well as apparent pleiotropy between variants influencing both cannabis dependence and major depressive disorder.

"These results … suggest that common pathways (nervous system development, inflammation, and ion homeostasis) mediate the risk for multiple psychiatric disorders and dependence on multiple substances, including cannabis," senior author Joel Gelernter, a psychiatry researcher at the Yale University School of Medicine, and his co-authors wrote in their paper.

To search for associations with cannabis dependence, Gelernter and his colleagues scrutinized SNPs that were directly genotyped on arrays or imputed with help from 1000 Genomes Project data for 14,754 study participants, including 6,000 African Americans and 8,754 individuals of European descent who were enrolled in three different substance dependence studies. They noted that around 18 percent to 36 percent of participants from each cohort had cannabis dependence symptoms.

A comparison of variant patterns in those with or without the condition in discovery and replication analyses pointed to three loci with possible associations to cannabis dependence: SNPs in the antisense transcript RP11-206M11.7, the SLC35G1 gene, and the CSMD1 gene.

Variants in the RIMS2 and MEF2C genes, which have been implicated in schizophrenia risk, showed more questionable ties to cannabis dependence risk, while nearly 2 percent of the genetic signal the researchers saw for cannabis dependence overall seemed to overlap with those contributing to genetic risk of major depressive disorder.

The results are intriguing, since past studies have described enhanced rates of depression in frequent cannabis users and higher-than-usual schizophrenia risk in individuals who use cannabis as children or adolescents. The study's authors noted that such overlap may reflect roles for some of the same pathways in psychiatric conditions and drug dependence, including processes related to brain development, synaptic signaling, and immune responses.

They also explained, however, that individuals from cannabis dependence cohorts may be more likely to depend on other substances as well, making it tricky to attribute genetic associations with cannabis dependence specifically.

In an accompanying editorial, Cardiff University researchers urged caution in interpreting potential overlap between cannabis dependence and psychiatric conditions, given the range in the severity of cannabis dependence symptoms in participants profiled, along with the presence of other drug use that might influence the apparent associations. Along with replication of the findings, they noted that further research is needed to untangle the functional effects of different cannabis dependence and psychiatric condition-related variants that fall in the same genes.