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Results for “quantitative trait locus”

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PubMed2002

Barley Cbf3 gene identification, expression pattern, and map location.

Although cold and drought adaptation in cereals and other plants involve the induction of a large number of genes, inheritance studies in Triticeae (wheat [Triticum aestivum], barley [Hordeum vulgare], and rye [Secale cereale]) have revealed only a few major loci for frost or drought tolerance that are consistent across multiple genetic backgrounds and environments. One might imagine that these loci could encode highly conserved regulatory factors that have global effects on gene expression; therefore, genes encoding central regulators identified in other plants might be orthologs of these Triticeae stress tolerance genes. The CBF/DREB1 regulators, identified originally in Arabidopsis as key components of cold and drought regulation, merit this consideration. We constructed barley cDNA libraries, screened these libraries and a barley bacterial artificial chromosome library using rice (Oryza sativa) and barley Cbf probes, found orthologs of Arabidopsis CBF/DREB1 genes, and examined the expression and genetic map location of the barley Cbf3 gene, HvCbf3. HvCbf3 was induced by a chilling treatment. HvCbf3 is located on barley chromosome 5H between markers WG364b and saflp58 on the barley cv Dicktoo x barley cv Morex genetic linkage map. This position is some 40 to 50 cM proximal to the winter hardiness quantitative trait locus that includes the Vrn-1H gene, but may coincide with the wheat 5A Rcg1 locus, which governs the threshold temperature at which cor genes are induced. From this, it remains possible that HvCbf3 is the basis of a minor quantitative trait locus in some genetic backgrounds, though that possibility remains to be thoroughly explored.

Amino Acid Sequence↗

PubMed2003

Linkage and association analysis of nevus density and the region containing the melanoma gene CDKN2A in UK twins.

Rare mutations in the CDKN2A gene are highly penetrant for melanoma. Density of nevi is under strong genetic control and high density is a potent risk factor for melanoma. We used linkage and association analysis in adolescent twins from the UK to examine the hypothesis that the region containing the CDKN2A gene also contains a quantitative trait locus influencing normal nevus development. Five markers in the CDKN2A region were genotyped in 115 dizygotic twin pairs, and one marker (D9S942) was genotyped in 103 monozygotic twin pairs, all of whom had been phenotyped for nevus density. Linkage analysis showed no evidence of a quantitative trait locus influencing nevus density in this chromosomal region. A model partitioning the variation in phenotype into within- and between-twin pair components showed weak evidence of association between higher nevus density and longer mean length of the two D9S942 alleles (P=0.01). This relation, which was also observed in an earlier Australian twin study, could be because of the linkage disequilibrium between D9S942 and a neighbouring functional locus. Further investigation of this region is warranted in large-scale linkage or association studies.

Adolescent↗

PubMed2006

Physical map of the wheat high-grain protein content gene Gpc-B1 and development of a high-throughput molecular marker.

Grain protein content (GPC) is important for human nutrition and has a strong influence on pasta and bread quality. A quantitative trait locus, derived from a Triticum turgidum ssp. dicoccoides accession (DIC), with an average increase in GPC of 14 g kg(-1) was mapped on chromosome 6BS. Using the wheat-rice colinearity, a high-density map of the wheat region was developed and the quantitative trait locus was mapped as a simple Mendelian locus designated Gpc-B1. A physical map of approx. 250 kb of the Gpc-B1 region was developed using a tetraploid wheat bacterial artificial chromosome library. The constructed physical map included the two Gpc-B1 flanking markers and one potential candidate gene from the colinear rice region completely linked to Gpc-B1. The relationship between physical and genetic distances and the feasibility of isolating genes by positional cloning in wheat are discussed. A high-throughput codominant marker, Xuhw89, was developed. A 4-bp deletion present in the DIC allele was absent in a collection of 117 cultivated tetraploid and hexaploid wheat germplasm, suggesting that this marker will be useful to incorporate the high GPC allele from the DIC accession studied here into commercial wheat varieties.

Chromosomes, Plant↗

PubMed1998

Genetic mapping of soluble guanylyl cyclase genes: implications for linkage to blood pressure in the Dahl rat.

The nitric oxide (NO) signaling system, consisting of NO synthases, soluble guanylyl cyclase, and cGMP, plays a prominent role in salt handling and regulation of blood pressure. Soluble guanylyl cyclases are heme-containing heterodimers (alpha/beta). The alpha1/beta1 isoform has greater NO sensitivity than the alpha1/beta2. It has recently been shown that expression of the beta subunits is altered in the kidney of the Dahl salt-sensitive rat, ie, the beta1 subunit is decreased and the beta2 subunit increased. However, whether soluble guanylyl cyclase is linked to salt sensitivity is not known. In the present study, we investigated linkage of guanylyl cyclase genes to blood pressure. Alpha1 and beta1 gene loci for soluble guanylyl cyclase were mapped to rat chromosome 2, and the beta2 gene locus was mapped to rat chromosome 5 using fluorescent in situ metaphase hybridization. By use of a rat radiation hybrid panel, the gene loci were then further mapped with respect to known quantitative trait locus markers of salt-sensitive hypertension in the Dahl rat on chromosomes 2 and 5. Genes for alpha1 and beta1 were closely linked by two-point analysis to Na+,K+-ATPase alpha1 isoform (LOD of 15.1 and 14.0, respectively) and calmodulin-dependent protein kinase II-delta loci (LOD of 14.3 and 12.9, respectively), which have been previously shown to flank a quantitative trait locus for blood pressure in the Dahl rat. The alpha1 and beta1 genes were closely linked (LOD of 11.3; theta, 0.4). The beta2 gene locus was closely linked to the endothelin-2 (ET-2) locus (LOD of 13.0), which has been shown to cosegregate with blood pressure. We conclude that soluble guanylyl cyclase subunit loci, ie, alpha1, beta1, and beta2, are good candidates for genes controlling salt-sensitive hypertension in the Dahl rat.

Animals↗

PubMed1997

Common quantitative trait loci for alcohol-related behaviors and central nervous system neurotensin measures: locomotor activation.

We have analyzed LSXSS recumbinant inbred for ethanol-induced activity using 2.0 g/kg ethanol and a new method we call ethanol activation slope. The ethanol activation slope provides a robust dose-response measure of ethanol activation, independent of both activity after saline and the inhibitory effects of ethanol on locomotor activity. These behavioral data were used in a quantitative trait locus analysis to map chromosomal loci involved in ethanol-induced locomotor activity. We tentatively identified seven loci that mediate the low-dose stimulatory effect of ethanol and six loci involved in locomotion after 2.0 g/kg ethanol. Only one of the loci are in common between the two behaviors. We also compared the behavioral quantitative trait locus to those previously identified that are involved in regulating central nervous system neurotensin levels and neurotensin receptor densities. Six chromosomal regions were identified that regulate at least one central nervous system neurotensin measure and an ethanol-induced locomotor behavior. The identification of loci controlling both central nervous system neurotensin levels or neurotensin receptor densities and ethanol-induced locomotor activity strengthens the proposal that neurotensin regulates, in part, ethanol-induced behaviors and central nervous system sensitivity to ethanol.

Alcoholism↗

PubMed2005

New approaches to the genetic analysis of neuroticism and anxiety.

The completion of the human genome project and the complementary genome projects for other species has broadened the scope for novel bioinformatic approaches to quantitative trait locus (QTL) identification. A key issue for quantitative trait nucleotide (QTN) identification is progressing from a large QTL peak, spanning perhaps 50 cM and many hundreds of genes, to a gene or nucleotide variant which is responsible for that QTL effect. The complementary use of mouse models to dissect large syntenic loci in humans is a powerful method for reducing QTL intervals to the order of 1 Mb. This paper presents an overview of the approaches used in our laboratory to ultra-fine map QTLs for anxiety-related traits, and to identify quantitative trait genes (QTG). As new genetic techniques and statistical approaches arise, we are getting closer to identifying those long sought after QTNs.

Animals↗

PubMed2005

Attack behaviors in mice: from factorial structure to quantitative trait loci mapping.

The emergence or non-emergence of attack behavior results from interaction between the genotype and the conditions under which the mice are tested. Inbred mice of the same strain reared or housed under conditions do not react the same way; reactions also vary according to the place selected for testing and the different opponents. A factor analysis showed that the attack behavior in non-isolated males, tested in neutral area covaried with high testosterone and steroid sulfatase and low brain 5-hydroxytriptamine (5-HT), beta-endorphin and Adrenocorticotropic Hormone (ACTH) concentration, whereas, for isolated males tested in their own housing cage, it covaried with high testosterone activity and low brain 5-HT concentration. A wide genome scan was performed with two independent populations derived from C57BL/6J and NZB/BlNJ, each being reared, housed and tested under highly contrasting conditions, as described above, and confronted with A/J standard males. Common Quantitative Trait Loci emerged for two rearing/testing conditions. For rattling latency we detected Quantitative Trait Loci on Mus musculus chromosome 8 (MMU8) (at 44, LOD score=3.51 and 47 cM, LOD score=6.22, for the first and the second conditions) and on MMU12 (at 39 cM, LOD score=3.69 and at 41 cM, LOD score=2.99, respectively). For the number of attacks, Quantitative Trait Loci were common: on MMU11 at 39 cM LOD score=4.51 and 45 cM, LOD score=3.05, respectively, and on MMU12 (17 cM, LOD score=2.71 and 24 cM, LOD score=3.10). The steroid sulfatase gene (Sts), located on the X-Y pairing region, was linked, but only in non-isolated males, tested in neutral area for rattling latency, first attack latency, and number of attacks (LOD scores=4.9, 4.79 and 3.57, respectively). We found also that the Quantitative Trait Locus encompassing Sts region interacted with other Quantitative Trait Loci. These results indicate that attack behavior measured in different rearing and testing conditions have different biological and genetic correlates. This suggests that further explorations should be done with standardized tests and, in addition, with a wide range of tests, so as to gain an understanding of the true impact of genes or pharmacological treatments on specific categories of aggressive behavior.

Aggression↗

PubMed1995

Cold-Specific Induction of a Dehydrin Gene Family Member in Barley.

An interval on barley (Hordeum vulgare L.) chromosome 7 accounting for significant quantitative trait locus effects for winter hardiness were detected in a winter (Dicktoo) x spring (Morex) barley population (P.M. Hayes, T. Blake, T.H.H. Chen, S. Tragoonrung, F. Chen, A. Pan, and B. Liu [1993] Genome 36: 66-71). Two members of the barley dehydrin gene family, Dhn1 and Dhn2, were located within the region defining the winter hardiness quantitative trait locus effect (A. Pan, P.M. Hayes, F. Chen, T. Blake, T.H.H. Chen, T.T.S. Wright, I. Karsai, Z. Bedo [1994] Theor Appl Genet 89: 900-910). To investigate the possible role of Dhn1 and Dhn2 in winter hardiness, we examined the expression pattern of six barley dehydrin gene family members in shoot tissue in response to cold temperature. Incubation of 3-week-old barley plants at 2[deg]C resulted in a rapid induction of a single 86-kD polypeptide that was recognized by an antiserum against a peptide conserved in the dehydrin gene family. Northern blot analysis confirmed the induction of an mRNA corresponding to Dhn5. The expression patterns of cold-induced dehydrins in shoot tissue for Dicktoo and Morex were identical under the conditions studied, in spite of the known phenotypic differences in their winter hardiness. These results, together with the allelic structure of selected high- and low-survival lines, suggest that the Dicktoo alleles at the Dhn1 and Dhn2 may not be the primary determinants of winter hardiness in barley.

Journal Article↗

PubMed1998

Genetic evaluation by best linear unbiased prediction using marker and trait information in a multibreed population.

Genetic evaluation by best linear unbiased prediction (BLUP) requires modeling genetic means, variances, and covariances. This paper presents theory to model means, variances, and covariances in a multibreed population, given marker and breed information, in the presence of gametic disequilibrium between the marker locus (ML) and linked quantitative trait locus (MQTL). Theory and algorithms are presented to construct the matrix of conditional covariances between relatives (Gv) for the MQTL effects in a multibreed population and to obtain the inverse of Gv efficiently. Theory presented here accounts for heterogeneity of variances among pure breeds and for segregation variances between pure breeds. A numerical example was used to illustrate how the theory and algorithms can be used for genetic evaluation by BLUP using marker and trait information in a multibreed population.

Genetic Linkage↗

PubMed2001

Mapping and sequencing rat dishevelled-1: a candidate gene for cerebral ischaemic insult in a rat model of stroke.

A quantitative trait locus on chromosome 5 in the rat is linked to sensitivity to brain ischemia in the stroke-prone spontaneously hypertensive rat (SHRSP). The genes encoding atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) that map to this location have been excluded as candidate genes. We examined dishevelled-1 (DVL-1) as a further candidate gene. DVL-1 had not yet been identified in the rat, but Anp, Bnp, and DVL-1 map to the homologous regions of the rat chromosome 5 quantitative trait locus in both mice and man. Furthermore, DVL-1 is involved in the Notch signalling system, which plays a role in the disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the symptoms of, which include ischaemic stroke. We show with radiation hybrid mapping that rat DVL-1 indeed maps to chromosome 5, where it is positioned immediately next to microsatellite marker D5Rat49. We sequenced the complete coding sequence and a large part of the intronic genomic sequence for the SHRSP strain and its reference Wistar-Kyoto strain. The DVL-1 sequence in the two strains was identical. Our results essentially exclude the DVL-1 gene as the cause for sensitivity to cerebral ischaemic insult in this rat model of stroke.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Atherosclerosis quantitative trait loci are sex- and lineage-dependent in an intercross of C57BL/6 and FVB/N low-density lipoprotein receptor-/- mice.

Atherosclerosis is a complex disease that is affected by environmental as well as genetic factors. The aim of the present study was to identify loci of atherosclerosis susceptibility in a cross of atherosclerosis-susceptible C57BL/6 and atherosclerosis-resistant FVB/N mice on the low-density lipoprotein (LDL) receptor (LDLR)-deficient background (LDLR(-/-)) and to test whether these loci are affected by lineage. A total of 459 F(2)s were generated in two ways: In cross "mB6xfFVB," male B6.LDLR(-/-) mice were crossed to female FVB.LDLR(-/-) mice to generate 107 female and 112 male F(2)s. In cross "mFVBxfB6," male FVB.LDLR(-/-) mice were crossed to female B6.LDLR(-/-) mice to generate 120 female and 120 male F(2)s. Animals were phenotyped for cross-sectional atherosclerotic lesion area at the aortic root, and a genome scan was carried out with 192 microsatellite markers. Quantitative trait locus mapping revealed significant loci of atherosclerosis susceptibility on chromosomes 3, 10, and 12. On chromosome 10 maximal logarithm of odds (LOD) scores of 13.1 (D10Mit16, 16 cM) and 5.7 (D10Mit168, 9 cM) were found in female and male mice, respectively. On chromosome 3, a maximal LOD score of 5.1 (D3Mit45, 79 cM) was detected only in females. On proximal chromosome 12 significant LOD scores were lineage-dependent, with maximal LOD scores of 3.9 (D12Mit82, 3 cM) and 4.8 (D12Mit189, 24 cM) present only in female mice of cross mB6xfFVB and male mice of cross mFVBxfB6, respectively. We conclude that, in this intercross, loci of atherosclerosis susceptibility are in part sex- and lineage-dependent. Awareness of these complexities may have major consequences for the identification of atherosclerosis susceptibility genes by quantitative trait locus mapping.

Animals↗

PubMed2002

The complement factor 5a receptor gene maps to murine chromosome 7.

Complement factor 5a (C5a) promotes local inflammation and is a potent chemoattractant for neutrophils and macrophages. We had an interest in C5a and its receptor, C5r1, because we previously identified C5a as a positional candidate gene for the quantitative trait locus Abhr2, which determines allergen-induced bronchial hyperresponsiveness in our murine model of asthma. To study the significance of C5r1 in our asthma model we first had to determine its genomic map location in mice. Genomic sequence surrounding murine C5r1 was analyzed for polymorphisms and two variable microsatellites were identified. These microsatellites were genotyped in A/J x (C3H/HeJ x A/J)F1 backcross mice (n = 355) and mapped in a panel of 164 markers spaced at approximately 10 cM intervals throughout the genome. Multipoint linkage analysis placed C5r1 on murine chromosome 7, 3.9 cM from the top of the linkage group. This map location has been previously identified as containing an additional quantitative trait locus for allergen-induced airway hyperresponsiveness, Abhr3, in this population of mice.

Animals↗

PubMed1998

Genetic analysis of behavioral, neuroendocrine, and biochemical parameters in inbred rodents: initial studies in Lewis and Fischer 344 rats and in A/J and C57BL/6J mice.

Previous work has identified inherent behavioral, neuroendocrine, and biochemical differences among inbred rodent strains that have been related to the animals' differential responsiveness to drugs of abuse or stress. In the present study, we sought to determine (1) whether there are genetic correlations among particular phenotypic traits that differ between a pair of inbred rat strains (Lewis and Fischer 344) or a pair of inbred mouse strains (A/J and C57BL/6J); (2) which of these traits might be amenable to quantitative trait locus analysis; and (3) whether additional behavioral or biochemical differences relevant to drug- or stress-responsiveness could be identified in these strains. Specifically, we measured several behavioral, neuroendocrine, and biochemical traits in parental Lewis and Fischer 344 rats and in 298 members of an F2 intercross population, as well as in parental A/J and C57BL/6J mice and in 11 of the AXB/BXA recombinant inbred mouse strains. Traits measured included exploratory locomotor activity in a novel environment; amphetamine-induced locomotor activity; several specific protein levels in striatal regions, including inhibitory G protein subunits, the dopamine transporter, the Fos family member transcription factor DeltaFosB, and the protein phosphatase inhibitor DARPP-32; and late-afternoon plasma corticosterone concentrations. Each of the traits measured in F2 rats or recombinant inbred mice appears to be influenced by multiple genes, as well as by environmental factors. There were statistically significant, albeit relatively weak, correlations among several traits in an F2 intercross population bred from Lewis and Fischer rats. Among the traits studied in Lewis and Fischer rats, one seemed most amenable to quantitative trait locus analysis: the level of the inhibitory G-protein subunit, Galphai, in the nucleus accumbens. We also found a robust genetic correlation between levels of DeltaFosB and levels of the dopamine transporter in striatal regions in AXB/BXA recombinant inbred mouse strains. While these studies demonstrate the likely complexity of the genetic factors that influence the numerous phenotypes associated with altered responsiveness to drugs of abuse and stress, they represent an initial and necessary step toward identifying specific genetic factors involved.

Amphetamine↗

PubMed2002

Genetic analysis of traits distinguishing outcrossing and self-pollinating forms of currant tomato, Lycopersicon pimpinellifolium (Jusl.) Mill.

The evolution of inbreeding is common throughout the angiosperms, although little is known about the developmental and genetic processes involved. Lycopersicon pimpinellifolium (currant tomato) is a self-compatible species with variation in outcrossing rate correlated with floral morphology. Mature flowers from inbreeding and outcrossing populations differ greatly in characters affecting mating behavior (petal, anther, and style lengths); other flower parts (sepals, ovaries) show minimal differences. Analysis of genetic behavior, including quantitative trait locus (QTL) mapping, was performed on representative selfing and outcrossing plants derived from two contrasting natural populations. Six morphological traits were analyzed: flowers per inflorescence; petal, anther, and style lengths; and lengths of the fertile and sterile portions of anthers. All traits were smaller in the selfing parent and had continuous patterns of segregation in the F(2). Phenotypic correlations among traits were all positive, but varied in strength. Quantitative trait locus mapping was done using 48 RFLP markers. Five QTL total were found involving four of the six traits: total anther length, anther sterile length, style length, and flowers per inflorescence. Each of these four traits had a QTL of major (>25%) effect on phenotypic variance.

Chromosome Mapping↗

PubMed1998

Mapping of serum amylase-1 and quantitative trait loci for milk production traits to cattle chromosome 4.

The present study was undertaken to confirm and refine the mapping of a quantitative trait locus in cattle for milk fat percentage that had earlier been reported to be linked to the serum amylase-1 locus, AM1. Five half-sib families from the previous study and 7 new ones were genotyped for nine microsatellite markers spanning chromosome 4. AM1 was mapped between the microsatellite markers BMS648 and BR6303. In a granddaughter design, interval mapping based on multiple-marker regression was utilized for an analysis of five milk production traits: milk yield, fat percentage and yield, and protein percentage and yield. In the families reported on previously, significant effects for fat and protein percentages were detected. In the new families, an effect on milk and fat yields was found. The most likely positions of the quantitative trait locus in both groups of families were in the same area of chromosome 4 in the vicinity of the obese locus. Direct effects of the obese locus were tested for using polymorphism in two closely linked microsatellites located 2.5 and 3.6 top downstream of the coding sequence. No firm evidence was found for an association between the obese locus and the tested traits.

Amylases↗

PubMed2003

Genetic architecture of a selection response in Arabidopsis thaliana.

Quantitative trait locus (QTL) mapping has become an established and effective method for studying the genetic architecture of complex traits. In this report, we use a QTL mapping approach in combination with data from a large selection experiment in Arabidopsis thaliana to explore a response to selection of experimental populations with differentiated genetic backgrounds. Experimental populations with genetic backgrounds derived from ecotypes Landsberg and Niederzenz were exposed to multiple generations of fertility and viability selection. This selection resulted in phenotypic shifts in a number of life-history and fitness-related characters including early development time, flowering time, dry biomass, longevity, and fruit production. Quantitative trait loci were mapped for these traits and their positions were compared to previously characterized allele frequency changes in the experimental populations (Ungerer et al. 2003). Quantitative trait locus positions largely colocalized with genomic regions under strong and consistent selection in populations with differentiated genetic backgrounds, suggesting that alleles for these traits were selected similarly in differentiated genetic backgrounds. However, one QTL region exhibited a more variable response; being positively selected on one genetic background but apparently neutral in another. This study demonstrates how QTL mapping approaches can be combined with map-based population genetic data to study how selection acts on standing genetic variation in populations.

Analysis of Variance↗

PubMed2001

Neither the New Zealand genetically hypertensive strain nor Dahl salt-sensitive strain has an A1079T transversion in the alpha1 isoform of the Na(+),K(+)-ATPase gene.

A putative 1079A-->T mutation in the alpha1 isoform of the Na(+), K(+)-ATPase (Atp1a1) gene of the Dahl salt-sensitive rat inbred by John Rapp (SS/Jr) strain was projected to cause a conformation change in the membrane hydrophobic region of the protein product, possibly resulting in hypertension. The existence of the mutation was challenged, but the challenge was apparently rebutted. The New Zealand genetically hypertensive (GH) rat is known to have a blood pressure quantitative trait locus on chromosome 2 containing the gene for the ATPase. Thus, we sought to determine whether the GH rat carried the 1079A-->T transversion. We chose a method, first nucleotide change analysis, that can detect point mutations in a mixed population of polymerase chain reaction (PCR) products, even in the presence of PCR bias, and confirmed our analysis by restriction enzyme digestion of PCR products. To ensure the validity of our analyses, we used site-directed mutagenesis to create positive controls containing the mutation. Surprisingly, we found that neither the GH nor the SS/Jr strain had the A1079T transversion. Indeed, the transversion was not found in any strain tested. As an incidental observation, we have sequenced the intron preceding the exon containing the putative A1079T transversion. Within this intron, a single-base C/T polymorphism was observed at base 132. Our results definitively eliminate the putative A1079T transversion in Atp1a1 as a causative factor underlying hypertension in the GH, spontaneously hypertensive, and SS/Jr rat strains and indicate that alternative candidate genes in the region defined by the chromosome 2 hypertension quantitative trait locus should be examined.

Adenosine Triphosphate↗

PubMed2000

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

Low levels of dopamine beta-hydroxylase (DbetaH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DbetaH level is a stable, genetically controlled trait. DBH, the locus encoding DbetaH protein, is the major quantitative trait locus controlling plasma and CSF DbetaH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DbetaH 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 DbetaH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DbetaH levels, demonstrated that alleles of similar association to DbetaH 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 low-DbetaH-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 DbetaH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.

Alleles↗