Genome-Wide Association Study of d-Amphetamine Response in Healthy Volunteers Identifies Putative Associations, Including Cadherin 13 (CDH13)

Amy B Hart; Barbara E Engelhardt; Margaret C Wardle; Greta Sokoloff; Matthew Stephens; Harriet de Wit; Abraham A Palmer

doi:10.1371/journal.pone.0042646

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Genome-Wide Association Study of d-Amphetamine Response in Healthy Volunteers Identifies Putative Associations, Including Cadherin 13 (CDH13)

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Genome-Wide Association Study of d-Amphetamine Response in Healthy Volunteers Identifies Putative Associations, Including Cadherin 13 (CDH13)

Amy B Hart, Barbara E Engelhardt, Margaret C Wardle, Greta Sokoloff, Matthew Stephens, Harriet de Wit and Abraham A Palmer

PloS one, Vol.7(8), pp.e42646-e42646

08/28/2012

DOI: 10.1371/journal.pone.0042646

PMCID: PMC3429486

PMID: 22952603

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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 x 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-alpha-polypeptide-1 (SRD5A1; P = 2.53 x 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.

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Title: Subtitle: Genome-Wide Association Study of d-Amphetamine Response in Healthy Volunteers Identifies Putative Associations, Including Cadherin 13 (CDH13)
Creators: Amy B Hart - University of Chicago
Barbara E Engelhardt - University of Chicago
Margaret C Wardle - University of Chicago
Greta Sokoloff - University of Chicago
Matthew Stephens - University of Chicago
Harriet de Wit - University of Chicago
Abraham A Palmer - University of Chicago
Resource Type: Journal article
Publication Details: PloS one, Vol.7(8), pp.e42646-e42646
DOI: 10.1371/journal.pone.0042646
PMID: 22952603
PMCID: PMC3429486
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: PUBLIC LIBRARY SCIENCE
Number of pages: 10
Grant note: Bioinformatics Research Development Fund DA007255; HG006265; HG002585; DA02812; DA021336; DA024845 / NIH
Language: English
Date published: 08/28/2012
Academic Unit: Psychological and Brain Sciences
Record Identifier: 9984256932502771

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