Ventral midbrain correlation between genetic variation and expression of the dopamine transporter gene in cocaine-abusing versus non-abusing subjects.
Altered activity of the human dopamine transporter gene (hDAT) is associated with several common and severe brain disorders, including cocaine abuse. However, there is little a priori information on whether such alterations are due to nature (genetic variation) or nurture (human behaviors such as cocaine abuse). This study investigated the correlation between seven markers throughout hDAT and its mRNA levels in postmortem ventral midbrain tissues from 18 cocaine abusers and 18 strictly matched drug-free controls in the African-American population. Here, we show that one major haplotype with the same frequency in cocaine abusers versus drug-free controls displays a 37.1% reduction of expression levels in cocaine abusers compared with matched controls (P=0.0057). The most studied genetic marker, variable number tandem repeats (VNTR) located in Exon 15 (3'VNTR), is not correlated with hDAT mRNA levels. A 5' upstream VNTR (rs70957367) has repeat numbers that are positively correlated with expression levels in controls (r(2)=0.9536, P=0.0235), but this positive correlation disappears in cocaine abusers. The findings suggest that varying hDAT activity is attributable to both genetics and cocaine abuse.
Department of Psychiatry, Harvard Medical School and Division of Alcohol and Drug Abuse, McLean Hospital, Belmont, MA, USA Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA Department of Statistics, Harvard University, Cambridge, MA, USA.
Yanhong
Y
Zhou
Sharon K
SK
Michelhaugh
Carl J
CJ
Schmidt
Jun S
JS
Liu
Michael J
MJ
Bannon
Zhicheng
Z
Lin
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D016022:Case-Control Studies; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D005819:Genetic Markers; D012333:RNA, Messenger