The AVPR1A Gene and Substance Use Disorders: Association, Replication, and Functional Evidence

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• 作者：Brion S.  ; Maher^a ;   ; ^{bmaher@jhsph.edu} ; Vladimir I.  ; Vladimirov^a ; Shawn J.  ; Latendresse^a ; Dawn L.  ; Thiselton^a ; Rebecca  ; McNamee^b ; Moonsu  ; Kang^a ; Tim B.  ; Bigdeli^a ; Xiangning  ; Chen^a ; Brien P.  ; Riley^a ; John M.  ; Hettema^a ; Howard  ; Chilcoat^e ; Christian  ; Heidbreder^e ; Pierandrea  ; Muglia^e ; E. Lenn  ; Murrelle^e ; Danielle M.  ; Dick^a ; Fazil  ; Aliev^a ; Arpana  ; Agrawal^f ; Howard J.  ; Edenberg^g ; John  ; Kramerⁱ ; John  ; Nurnberger^h ; Jay A.  ; Tischfield^j ; Bernie  ; Devlin^b ;   ; ^c ; Robert E.  ; Ferrell^b ;   ; ^d ; Galina P.  ; Kirillova^b ; Ralph E.  ; Tarter^b ;   ; ^c ; Kenneth S.  ; Kendler^a ; Michael M.  ; Vanyukov^b ;   ; ^c ;   ; ^d
• 关键词：Addiction ; alcoholism ; gene systems ; genetic association ; social relationships ; vasopressin
• 刊名：Biological Psychiatry
• 出版年：2011
• 出版时间：15 September 2011
• 年：2011
• 卷：70
• 期：6
• 页码：519-527
• 全文大小：461 K

文摘

Background

The liability to addiction has been shown to be highly genetically correlated across drug classes, suggesting nondrug-specific mechanisms.

Methods

In 757 subjects, we performed association analysis between 1536 single nucleotide polymorphisms (SNPs) in 106 candidate genes and a drug use disorder diagnosis (DUD).

Results

Associations (p ?.0008) were detected with three SNPs in the arginine vasopressin 1A receptor gene, AVPR1A, with a gene-wise p value of 3 ¡Á 10^?. Bioinformatic evidence points to a role for rs11174811 (microRNA binding site disruption) in AVPR1A function. Based on literature implicating AVPR1A in social bonding, we tested spousal satisfaction as a mediator of the association of rs11174811 with the DUD. Spousal satisfaction was significantly associated with DUD in males (p < .0001). The functional AVPR1A SNP, rs11174811, was associated with spousal satisfaction in males (p = .007). Spousal satisfaction was a significant mediator of the relationship between rs11174811 and DUD. We also present replication of the association in males between rs11174811 and substance use in one clinically ascertained (n = 1399) and one epidemiologic sample (n = 2231). The direction of the association is consistent across the clinically-ascertained samples but reversed in the epidemiologic sample. Lastly, we found a significant impact of rs11174811 genotype on AVPR1A expression in a postmortem brain sample.

Conclusions

The findings of this study call for expansion of research into the role of the arginine vasopressin and other neuropeptide system variation in DUD liability.