Abstract
Both the subjective response to d-amphetamine and the risk for amphetamine addiction are known to be heritable traits. Because subjective responses to drugs may predict drug addiction, identifying alleles that influence acute response may also provide insight into the genetic risk factors for drug abuse. We performed a Genome Wide Association Study (GWAS) for the subjective responses to amphetamine in 381 non-drug abusing healthy volunteers. Responses to amphetamine were measured using a double-blind, placebo-controlled, within-subjects design. We used sparse factor analysis to reduce the dimensionality of the data to ten factors. We identified several putative associations; the strongest was between a positive subjective drug-response factor and a SNP (rs3784943) in the 8th intron of cadherin 13 (CDH13; P = 4.58×10−8), a gene previously associated with a number of psychiatric traits including methamphetamine dependence. Additionally, we observed a putative association between a factor representing the degree of positive affect at baseline and a SNP (rs472402) in the 1st intron of steroid-5-alpha-reductase-α-polypeptide-1 (SRD5A1; P = 2.53×10−7), a gene whose protein product catalyzes the rate-limiting step in synthesis of the neurosteroid allopregnanolone. This SNP belongs to an LD-block that has been previously associated with the expression of SRD5A1 and differences in SRD5A1 enzymatic activity. The purpose of this study was to begin to explore the genetic basis of subjective responses to stimulant drugs using a GWAS approach in a modestly sized sample. Our approach provides a case study for analysis of high-dimensional intermediate pharmacogenomic phenotypes, which may be more tractable than clinical diagnoses.
Highlights
The subjective responses to amphetamine and the risk for amphetamine dependence are heritable traits [1,2,3]
Rs3784943 falls within the 8th intron of the gene cadherin 13 (CDH13) which codes for a cell adhesion molecule that is highly expressed in the brain [50]
We identified a single nucleotide polymorphisms (SNPs) in the CDH13 gene (Figure 2) that was associated with the degree of positive response to amphetamine
Summary
The subjective responses to amphetamine and the risk for amphetamine dependence are heritable traits [1,2,3]. Our study differs from most published GWAS in its use of complex multi-dimensional phenotypes rather than a binary diagnosis such as drug dependence or abuse. We obtained responses on three questionnaires, administered over six time points, in three sessions, after placebo or one of two doses of drug Such multi-dimensional ‘‘intermediate phenotypes’’ have many advantages over binary diagnoses. Intermediate phenotypes can be measured under carefully controlled conditions, e.g., laboratory conditions, and may be directly linked to genetic variants and resulting from specific biological processes. For this reason, intermediate phenotypes are hypothesized to show stronger genetic associations than binary diagnoses, potentially allowing for smaller sample sizes [22]. Association studies of the response to cisplatin [25], warfarin [26], nortriptyline [27], radiation therapy [28], pegylated interferon and ribavirin [29], and interferon-b [30] have all identified genomewide significant associations using small samples sizes
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