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Unformatted text preview: Variation in a bicarbonate co-transporter gene family member SLC4A7 is associated with propensity to addictions: a study using fine-mapping and three samples Hiroki Ishiguro 1,2 , Donna Walther 1 , Tadao Arinami 2 & George R. Uhl 1 Molecular Neurobiology Branch, NIH-IRP, NIDA, DHHS, Baltimore, MD, USA 1 and Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba,Tennoudai,Tsukuba, Ibaraki, Japan 2 ABSTRACT Aims Classical genetic studies consistently reveal substantial heritability for addictions. However, the genes that harbour the variations providing these genetic influences remain largely unknown. We have focused attention on ‘reproducible substance abuse vulnerability’ (rSA) genomic regions, where linkage and association studies performed in several population provide evidence for such variations. Design We nominated rSA1 on human chromosome 3p23 within a 5 Mb region. We sought to replicate this finding and identify variations within this region. Setting We examine the role of allelic variations in the SLC4A7 gene, a member of the bicarbonate co-transporter family that is expressed in tissues including brain and kidney. Participants A total of 1158 unrelated individuals with informed consent about the genetic study were recruited from three independent populations. Measurements The single nucleotide polymorphism (SNP) markers in the SLC4A7 gene were analysed by case–control study. Findings The rs3278 is associated reliably with substance abuse vulnerability in (1) a European American sample selected from pedigrees within the Collaborative Study on the Genetics of Alcoholism (COGA; nominal P = 0.03); (2) an African American sample recruited by the National Institute on Drug Abuse (NIDA; nominal P = 0.008); and (3) a NIDA European American sample ( P = 0.001). Conclusions While the current results do not exclude additional roles for allelic variants in nearby genes, they do suggest that SLC4A7 allelic variants might alter dispositions and/or excretion of drugs and neurotransmitters in brain and periphery in ways that could contribute to differential vulnerabilities to addictions. SLC4A7 is thus a novel candidate in the contribution to vulnerability to addictions. Keywords Bicarbonate co-transporter, drug abuse, pharmacogenetics. Correspondence to: Hiroki Ishiguro, Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki 305–8575, Japan. E-mail: [email protected] Submitted 9 May 2005; initial review completed 11 July 2005; final version accepted 1 March 2007 INTRODUCTION Genetic variations play major roles in human substance abuse vulnerabilities [1–14]. To identify chromosomal regions likely to harbour these genetic variations, we have performed association-based genome scanning studies and compared these results with data from linkage-based genome scans. Using both these methods, we have termed chromosomal regions that are associated...
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This note was uploaded on 10/16/2011 for the course PSYCH 101 taught by Professor Brown,b during the Spring '08 term at BYU.
- Spring '08