Variation in a bicarbonate co-transporter gene family member SLC4A7 is associated with propensity to addictions: a study using fine-mapping and three samples.
OBJECTIVE
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.


METHODS
We nominated rSA1 on human chromosome 3p23 within a 5 Mb region. We sought to replicate this finding and identify variations within this region.


METHODS
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.


METHODS
A total of 1158 unrelated individuals with informed consent about the genetic study were recruited from three independent populations.


METHODS
The single nucleotide polymorphism (SNP) markers in the SLC4A7 gene were analysed by case-control study.


RESULTS
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.
Ishiguro
Hiroki
H
Molecular Neurobiology Branch, NIH-IRP, NIDA, DHHS, Baltimore, MD, USA. hishigur@md.tsukuba.ac.jp
Walther
Donna
D
Arinami
Tadao
T
Uhl
George R
GR
D000328:Adult; D016739:Behavior, Addictive / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009710:Nucleotide Mapping; D027982:Sodium-Bicarbonate Symporters / Q000032:analysis / Q000235:genetics*; D019966:Substance-Related Disorders / Q000235:genetics*; D027981:Symporters / Q000032:analysis / Q000235:genetics*
C422022:SLC4A7 protein, human; D027982:Sodium-Bicarbonate Symporters; D027981:Symporters