A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia

被引:149
作者
Cubells, JF
Kranzler, HR
McCance-Katz, E
Anderson, GM
Malison, RT
Price, LH
Gelernter, J
机构
[1] VA Connecticut Hlth Care Syst, W Haven, CT 06516 USA
[2] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA
[3] Univ Connecticut, Ctr Hlth, Dept Psychiat, Farmington, CT 06030 USA
[4] Yale Child Study Ctr, W Haven, CT 06516 USA
[5] Connecticut Mental Hlth Ctr, New Haven, CT 06519 USA
关键词
psychotic disorders; substance-related disorders; central nervous system stimulants; norepinephrine; catecholamines; schizophrenia; alleles; genes;
D O I
10.1038/sj.mp.4000657
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Low levels of dopamine beta-hydroxylase (D beta H) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. D beta H level is a stable, genetically controlled trait. DBH, the locus encoding D beta H protein, is the major quantitative trait locus controlling plasma and CSF D beta H revels. We therefore hypothesized that DBH variants or haplotypes, associated with low levers of D beta H in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5'-ins/del, located approximately 3 kb 5' to the DBH transcriptional start site, significantly associates with plasma D beta H activity in European-Americans (n = 66), Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic Variant associated with D beta H levels, demonstrated that alleles of similar association to D beta H levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45), As predicted, the tow-D beta H-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia, We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to D beta H levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia.
引用
收藏
页码:56 / 63
页数:8
相关论文
共 48 条
[1]   Sensory gating and cocaine induced paranoia [J].
Boutros, N ;
Krystal, J ;
Gelernter, J .
BIOLOGICAL PSYCHIATRY, 1998, 43 :89S-89S
[2]  
BRADY K, 1990, AM J PSYCHIAT, V147, P1164
[3]  
BRADY KT, 1991, J CLIN PSYCHIAT, V52, P509
[4]   Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram [J].
Carroll, KM ;
Nich, C ;
Ball, SA ;
McCance, E ;
Rounsavile, BJ .
ADDICTION, 1998, 93 (05) :713-727
[5]  
COOPER JR, 1986, BIOCH BASIS NEUROPHA
[6]   LOCALIZATION OF THE HUMAN DOPAMINE BETA-HYDROXYLASE (DBH) GENE TO CHROMOSOME-9Q34 [J].
CRAIG, SP ;
BUCKLE, VJ ;
LAMOUROUX, A ;
MALLET, J ;
CRAIG, IW .
CYTOGENETICS AND CELL GENETICS, 1988, 48 (01) :48-50
[7]   Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies [J].
Crawley, JN ;
Belknap, JK ;
Collins, A ;
Crabbe, JC ;
Frankel, W ;
Henderson, N ;
Hitzemann, RJ ;
Maxson, SC ;
Miner, LL ;
Silva, AJ ;
Wehner, JM ;
WynshawBoris, A ;
Paylor, R .
PSYCHOPHARMACOLOGY, 1997, 132 (02) :107-124
[8]  
Cubells JF, 1997, AM J MED GENET, V74, P374, DOI 10.1002/(SICI)1096-8628(19970725)74:4<374::AID-AJMG7>3.0.CO
[9]  
2-P
[10]   Dopamine β-hydroxylase:: two polymorphisms in linkage disequilibrium at the structural gene DBH associate with biochemical phenotypic variation [J].
Cubells, JF ;
van Kammen, DP ;
Kelley, ME ;
Anderson, GM ;
O'Connor, DT ;
Price, LH ;
Malison, R ;
Rao, PA ;
Kobayashi, K ;
Nagatsu, T ;
Gelernter, J .
HUMAN GENETICS, 1998, 102 (05) :533-540