Abstract
Background
Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies
can provide insight into its biology.
Methods
We completed an OD genome-wide association study in 3058 opioid-exposed European Americans,
1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion
count.
Results
By meta-analysis of four cohorts, Yale-Penn 1 (n = 1388), Yale-Penn 2 (n = 996), Yale-Penn 3 (n = 98), and SAGE (Study of Addiction: Genetics and Environment) (n = 576), we identified a variant on chromosome 15, rs12442183, near RGMA, associated with OD (p = 1.3 × 10−8). The association was also genome-wide significant in Yale-Penn 1 taken individually
and nominally significant in two of the other three samples. The finding was further
supported in a meta-analysis of all available opioid-exposed African Americans (n = 2014 [1106 meeting DSM-IV OD criteria]; p = 3.0 × 10−3) from three cohorts; there was nominal significance in two of these samples. Thus,
of seven subsamples examined in two populations, one was genome-wide significant,
and four of six were nominally (or nearly) significant. RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance
protein. Risk allele rs12442183*T was correlated with higher expression of a specific
RGMA transcript variant in frontal cortex (p = 2 × 10−3). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Coexpression analysis of 1301 brain samples
revealed that RGMA messenger RNA expression was associated with that of four genes implicated in other
psychiatric disorders, including GRIN1.
Conclusions
This is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology.
Keywords
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Article info
Publication history
Published online: January 11, 2018
Accepted:
December 30,
2017
Received in revised form:
December 22,
2017
Received:
August 7,
2017
Identification
Copyright
© 2018 Society of Biological Psychiatry.
