TY - JOUR
T1 - Cannabinoid receptor genotype moderation of the effects of childhood physical abuse on anhedonia and depression
AU - Agrawal, Arpana
AU - Nelson, Elliot C.
AU - Littlefield, Andrew K.
AU - Bucholz, Kathleen K.
AU - Degenhardt, Louisa
AU - Henders, Anjali K.
AU - Madden, Pamela A.F.
AU - Martin, Nicholas G.
AU - Montgomery, Grant W.
AU - Pergadia, Michele L.
AU - Sher, Kenneth J.
AU - Heath, Andrew C.
AU - Lynskey, Michael T.
PY - 2012/7
Y1 - 2012/7
N2 - Context: The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited. Objectives: To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and to replicate this interaction in an independent sample. Design, Setting, and Participants: Genetic association study in 1041 young US women with replication in an independent Australian sample of 1428 heroindependent individuals as cases and 506 participants as neighborhood controls. Main Outcome Measures: Self-reported anhedonia and depression (with anhedonia). Results: In both samples, individuals who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with 1 or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in participants reporting childhood physical abuse, although 57.1% of those homozygous for the major allele reported anhedonia, only 28.6% of those who were carriers of the minor allele reported it (P=.01). The rs1049353 polymorphism also buffered the effects of childhood physical abuse on major depressive disorder; however, this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, in which minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse. Conclusions: Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer; hence, future studies should carefully examine its effect on expression and conformational variation in CNR1, particularly in relation to stress adaptation.
AB - Context: The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited. Objectives: To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and to replicate this interaction in an independent sample. Design, Setting, and Participants: Genetic association study in 1041 young US women with replication in an independent Australian sample of 1428 heroindependent individuals as cases and 506 participants as neighborhood controls. Main Outcome Measures: Self-reported anhedonia and depression (with anhedonia). Results: In both samples, individuals who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with 1 or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in participants reporting childhood physical abuse, although 57.1% of those homozygous for the major allele reported anhedonia, only 28.6% of those who were carriers of the minor allele reported it (P=.01). The rs1049353 polymorphism also buffered the effects of childhood physical abuse on major depressive disorder; however, this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, in which minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse. Conclusions: Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer; hence, future studies should carefully examine its effect on expression and conformational variation in CNR1, particularly in relation to stress adaptation.
UR - http://www.scopus.com/inward/record.url?scp=84863558278&partnerID=8YFLogxK
U2 - 10.1001/archgenpsychiatry.2011.2273
DO - 10.1001/archgenpsychiatry.2011.2273
M3 - Article
C2 - 22393204
AN - SCOPUS:84863558278
SN - 0003-990X
VL - 69
SP - 732
EP - 740
JO - Archives of General Psychiatry
JF - Archives of General Psychiatry
IS - 7
ER -