Search PubMed⌕ Search

Biomedical subjects

A J Pakstis

Publications and source records attributed to A J Pakstis.

At least 37 records · Page 2Linked to original sources
PubMed1998

A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus.

A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) -- TaqI "A", "B", and "D" sites -- and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P<0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI "B" and "A", was highly significant with D' values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI "B" site in all populations, with D' values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an "Out of Africa" model for recent human evolution.

Alleles↗
PubMed1998

A global haplotype analysis of the myotonic dystrophy locus: implications for the evolution of modern humans and for the origin of myotonic dystrophy mutations.

Haplotypes consisting of the (CTG)n repeat, as well as several flanking markers at the myotonic dystrophy (DM) locus, were analyzed in normal individuals from 25 human populations (5 African, 2 Middle Eastern, 3 European, 6 East Asian, 3 Pacific/Australo-Melanesian, and 6 Amerindian) and in five nonhuman primate species. Non-African populations have a subset of the haplotype diversity present in Africa, as well as a shared pattern of allelic association. (CTG)18-35 alleles (large normal) were observed only in northeastern African and non-African populations and exhibit strong linkage disequilibrium with three markers flanking the (CTG)n repeat. The pattern of haplotype diversity and linkage disequilibrium observed supports a recent African-origin model of modern human evolution and suggests that the original mutation event that gave rise to DM-causing alleles arose in a population ancestral to non-Africans prior to migration of modern humans out of Africa.

Alleles↗
PubMed1997

The dopamine D4 receptor gene (DRD4) is not associated with alcoholism in three Taiwanese populations: six polymorphisms tested separately and as haplotypes.

The dopaminergic system has been implicated in alcoholism but studies at the dopamine D2 receptor gene (DRD2), one of the five dopamine receptors, have not given a consistent picture of an association with alcoholism. We have now studied the dopamine D4 receptor gene (DRD4) using six polymorphisms, both separately and as haplotypes. Three groups of alcoholics from Taiwan (Atayal, Ami, and Han) diagnosed as having severe alcohol dependence using DSM-III-R criteria, together with nonalcoholics matched for gender, ethnic group, and geographic origin, were typed by polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymorphism (RFLP) for all six polymorphisms. Three out of six markers are polymorphic in all three Taiwanese populations. Although the prevalence rates of alcoholism are remarkably different, no highly significant association of this locus with alcoholism was observed in any of the three groups whether the analysis considered genotype distributions or allele frequencies at the three polymorphic markers considered individually and as haplotypes. Neither is there any obvious pattern in the data that covaries with or hints at a relationship with the very different prevalences of alcoholism in the groups studied. Especially because the powerful, multi-site haplotype analysis was not statistically significant in any of the population samples, we conclude that there is no association of the DRD4 locus with alcoholism in Taiwanese populations.

Alcoholism↗
PubMed1996

No association between alcoholism and multiple polymorphisms at the dopamine D2 receptor gene (DRD2) in three distinct Taiwanese populations.

This study examined whether there is evidence for an association between alcoholism and the alleles of the TaqI A, TaqI B, and short tandem repeat polymorphisms (STRP), both individually and as haplotypes, at the dopamine D2 receptor gene (DRD2) in males of three populations from Taiwan. We studied 46 Chinese Han (21 alcoholics and 25 nonalcoholics), 42 Atayal (21 alcoholics and 21 nonalcoholics), and 40 Ami (20 alcoholics and 20 nonalcoholics). Alcoholism was diagnosed according to DSM-III-R criteria and all individuals in the alcoholic groups were severely affected. Significant linkage disequilibrium occurs for the three polymorphic sites in all three populations. No significant association was observed between any of the three polymorphisms at the DRD2 locus, tested individually and as haplotypes, and alcoholism in the three subject groups. We conclude that no association exists between genetic variation at the DRD2 locus and alcoholism in Chinese Han, Atayal, and Ami males.

Adult↗
PubMed1996

Global patterns of linkage disequilibrium at the CD4 locus and modern human origins.

Haplotypes consisting of alleles at a short tandem repeat polymorphism (STRP) and an Alu deletion polymorphism at the CD4 locus on chromosome 12 were analyzed in more than 1600 individuals sampled from 42 geographically dispersed populations (13 African, 2 Middle Eastern, 7 European, 9 Asian, 3 Pacific, and 8 Amerindian). Sub-Saharan African populations had more haplotypes and exhibited more variability in frequencies of haplotypes than the Northeast African or non-African populations. The Alu deletion was nearly always associated with a single STRP allele in non-African and Northeast African populations but was associated with a wide range of STRP alleles in the sub-Saharan African populations. This global pattern of haplotype variation and linkage disequilibrium suggests a common and recent African origin for all non-African human populations.

Africa↗
PubMed1996

PhenoDB: an integrated client/server database for linkage and population genetics.

In this paper we describe PhenoDB, an Internet-accessible client/server database application for population and linkage genetics. PhenoDB stores genetic marker data on pedigrees and populations. A database for population and linkage genetics requires two core functions: data management tasks, such as interactive validation during data entry and editing, and data analysis tasks, such as generating summary population statistics and performing linkage analyses. In PhenoDB we attempt to make these tasks as easy as possible. The client/server architecture allows efficient management and manipulation of large datasets via an easy-to-use graphical interface. PhenoDB data (73 populations, 34 pedigrees, approximately 4200 individuals, and close to 80,000 typings) are stored in a generic format that can be readily exported to (or imported from) the file formats required by various existing analysis programs such as LIPED and Lathrop and Lalouel's Multipoint Linkage. PhenoDB allows performance of complex ad-hoc queries and can generate reports for use in project management. Finally, PhenoDB can produce statistical summaries such as allele frequencies, phenotype frequencies, and Chi-square tests of Hardy-Weinberg ratios of population/pedigree data.

Alleles↗
PubMed1996

The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus.

The dopamine D4 receptor gene (DRD4) has an expressed polymorphism in the third exon that may have functional relevance. The polymorphism exists at two levels. At the higher level there is an imperfect tandem repeat of 48 base pairs (bp) coding for 16 amino acids; alleles have been identified with 2 (32 amino acids) to 10 (160 amino acids) repeats. The imperfect nature of the repeats is responsible for a more subtle level of variation since alleles with the same number of repeats can differ in the exact sequences or in the order of the variants of the 48-bp unit. We have undertaken a global survey of this expressed polymorphism as one approach to understanding the evolutionary significance and origins of the polymorphism as well as understanding what selective forces, if any, may be operating at this locus. As the first step, we have determined the repeat number genotype of the DRD4 repeat polymorphism in 1,327 individuals from 36 different populations. The allele frequencies differ considerably among the different populations. The 4-repeat allele was the most prevalent (global mean allele frequency = 64.3%) and appeared in every population with a frequency ranging from 0.16 to 0.96. The 7-repeat allele was the second most common (global mean = 20.6%), appearing quite frequently in the Americas (mean frequency = 48.3%) but only occasionally in East and South Asia (mean frequency = 1.9%). The 2-repeat allele was the third most common (global mean frequency = 8.2%) and was quite frequent in East and South Asia (mean frequency = 18.1%) while uncommon in the Americas (mean frequency = 2.9%) and Africa (mean frequency = 1.7%). The universality of the polymorphism with only three common repeat-number alleles (4, 7, and 2) indicates that the polymorphism is ancient and arose before the global dispersion of modern humans. The diversity of actual allele frequencies for this expressed polymorphism among different populations emphasizes the importance of population considerations in the design and interpretation of any association studies carried out with this polymorphism.

Africa↗
PubMed1996

DRD2 haplotypes containing the TaqI A1 allele: implications for alcoholism research.

In recent years, a possible role of the dopamine D2 receptor (DRD2) locus in the etiology of alcoholism has been the focus of considerable attention. The literature now contains a mix of association studies with positive and negative conclusions. Various methodological flaws undermine the claims in many of the studies that conclude a positive association exists between alcoholism and the DRD2*A1 allele at the Taql "A" site. Although the studies with negative findings have more often come from studies using better analytic methodology, satisfactory resolution of whether or not genetic variation at the DRD2 locus plays some role in the etiology of alcoholism is unlikely to come from additional studies of the kind conducted thus far; an approach enlightened by a more thorough understanding of the population genetics of DRD2 and the phylogenetic origins of the DRD2 alleles is one alternative. If genetic variation at the DRD2 locus affects susceptibility to alcoholism, then such variation has a mutational and evolutionary history that can be traced with the aid of the various genetic polymorphisms that have been identified at the DRD2 locus. In this study, a third Taql restriction fragment-length polymorphism at DRD2, the Taql "D" site, has been converted to polymerase chain reaction-based typing and its frequencies determined in 22 populations from around the world. Haplotypes defined by the polymorphisms at the Taql "B" and "A" sites, and the short tandem repeat polymorphism in intron 2 have been constructed and the diversity of haplotypes containing the DRD2*A1 allele examined for all 22 populations. The ancestral origins of the three Taql polymorphisms have also been determined by sequencing the homologous regions in other higher primates. Because A1-containing haplotypes in populations of European, Middle Eastern, and African origin show considerable diversity within and among populations, properly designed association studies in populations descended from those areas of the world need to use haplotypes, not a single allelic system, and need to use appropriate methods to compensate for the near impossibility of genetically matching unrelated control samples.

Alcoholism↗
PubMed1996

Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette syndrome, by the transmission-disequilibrium test.

Dopaminergic abnormalities are implicated in the pathogenesis of Tourette syndrome (TS) and chronic multiple tics. We used the transmission-disequilibrium test (TDT) method to test for linkage disequilibrium between a specific allele (the seven-repeat allele (DRD4*7R) of the exon 3 VNTR polymorphic site) at the D4 dopamine receptor locus (DRD4) and expression of chronic multiple tics and TS. This particular allele had been shown in functional studies to have different binding properties compared with the other common alleles in this DRD4 polymorphic system. We studied 64 family trios (consisting of an affected person and two parents, at least one heterozygous for DRD4*7R), including 12 nuclear family trios and 52 trios from four large TS kindreds. The DRD4*7R allele was transmitted significantly more frequently than expected (chi 2 TDT ranging from 8.47 [P < .004] to 10.80 [P = .001], depending on breadth of disease definition and inclusion or exclusion of inferred genotypes). Confirmation of this finding will depend on either replication in other samples or the identification of a transmitted functional mutation within this sample.

Alleles↗
PubMed1995

The dopamine transporter protein gene (SLC6A3): primary linkage mapping and linkage studies in Tourette syndrome.

The dopamine transporter, the molecule responsible for presynaptic reuptake of dopamine and a major site of action of psychostimulant drugs, including cocaine, is encoded by locus SLC6A3 (alias DAT1). The protein's actions and DAT's specific localization to dopaminergic neurons make it a candidate gene for several psychiatric illnesses. Alleles at this locus have been reported to be associated with cocaine-induced paranoia and attention deficit disorder. SLC6A3 has been mapped to distal chromosome 5p, using physical methods. Our goal was to place SLC6A3 in the genetic linkage map and to test for linkage to Tourette syndrome. Genetic linkage methods were used to place SLC6A3 in the genetic linkage map. Four extended pedigrees (one of which overlaps with CEPH) were typed. Linkage with Tourette syndrome (TS) was also examined. SLC6A3 showed close linkage with several markers previously mapped to distal chromosome 5p, including D5S11 (Zmax = 16.0, theta M = theta F = 0.03, results from four families) and D5S678 (Zmax = 7.84, theta M = theta F = 0, results from two families). Observed crossovers established that SLC6A3 is a distal marker close to D5S10 and D5S678, but these three distal markers could not be ordered. Linkage between TS and SLC6A3 could be excluded independently in two branches of a large kindred segregating TS; the lod score in a third family was also negative, but not significant. Cumulative results show a lod score of -6.2 at theta = 0 and of -3.9 at theta = 0.05 (dominant model, narrow disease definition). SLC6A3 thus maps to distal chromosome 5p by linkage analysis, in agreement with previous physical mapping data. A mutation at SLC6A3 is not causative for TS in the two large families that generated significant negative lod scores (if the parameters of our analyses were correct) and is unlikely to be causative in the family that generated a negative lod score that did not reach significance. These results do not exclude a role for the dopamine transporter in influencing risk for TS in combination with other loci.

Carrier Proteins↗
PubMed1995

Dinucleotide polymorphism at the DXS1178 locus is tightly linked to PGK1 at Xq13.

A polymorphic CA repeat (locus name DXS1178) was isolated from a 1-megabase YAC (OTCC) containing the OTC gene, located at Xp21.1. However, amplification in human-rodent hybrid cells and segregation analysis in three CEPH families mapped the DXS1178 locus at Xq13. The mapping ambiguity is apparently caused by the chimeric nature of the OTCC YAC clone.

Alleles↗
PubMed1995

Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17.

Abnormalities in monoamine metabolism, including serotonin metabolism, have been implicated in the pathophysiology of affective disorders, schizophrenia, suicide, and other psychiatric disorders. Serotonin transporter protein (SERT) allows neurons to retrieve serotonin that has been released into a synapse. SERT is a site of action for several drugs with CNS effects, including both therapeutic agents (e.g., antidepressants) and drugs of abuse (e.g., cocaine). This gene had previously been physically mapped to chromosome 17. We used a PCR product corresponding to the 3' untranslated region of the gene as a probe to identify restriction fragment length polymorphism (RFLP), which we then used to establish that the SLC6A4, genetic locus for SERT, is near 17q12 and probably flanked by D17S58 and D17S73 (a location consistent with observed crossovers). These data should be useful for linkage studies of neuropsychiatric disorders.

Carrier Proteins↗
PubMed1995

Linkage studies on Gilles de la Tourette syndrome: what is the strategy of choice?

For a linkage study it is important to ascertain family material that is sufficiently informative. The statistical power of a linkage sample can be determined via computer simulation. For complex traits uncertain parameters such as incomplete penetrance, frequency of phenocopies, gene frequency and variable expression have to be taken into account. One can either include only the most severe phenotype in the analysis or apply multiple linkage tests for a gradually broadened disease phenotype. Gilles de la Tourette syndrome (GTS) is a chronic neurological disorder characterized by multiple, intermittent motor and vocal tics. Segregation analyses suggest that GTS and milder phenotypes are caused by a single dominant gene. We report here the results of an extensive simulation study on a large set of families. We compared the effectiveness of linkage tests with only the GTS phenotype versus multiple tests that included various milder phenotypes and different gene frequencies. The scenario of multiple tests yielded superior power. Our results show that computer simulation can indicate the strategy of choice in linkage studies of multiple, complex phenotypes.

Chromosome Mapping↗
PubMed1995

Evolution of haplotypes at the DRD2 locus.

We present here the first evolutionary perspective on haplotypes at DRD2, the locus for the dopamine D2 receptor. The dopamine D2 receptor plays a critical role in the functioning of many neural circuits in the human brain. If functionally relevant variation at the DRD2 locus exists, understanding the evolution of haplotypes on the basis of polymorphic sites encompassing the gene should provide a powerful framework for identifying that variation. Three DRD2 polymorphisms (TaqI "A" and "B" RFLPs and the (CA)n short tandem repeat polymorphic in all the populations studied, and they display strong and significant linkage disequilibria with each other. The common haplotypes for the two TaqI RFLPs are separately derived from the ancestral haplotype but predate the spread of modern humans around the world. The knowledge of how the various haplotypes have evolved, the allele frequencies of the haplotypes in human populations, and the physical relationships of the polymorphisms to each other and to the functional parts of the gene should now allow proper design and interpretation of association studies.

Base Sequence↗
PubMed1994

Progress in a genome scan for linkage in schizophrenia in a large Swedish kindred.

Genetic linkage studies of a kindred from Sweden segregating for schizophrenia have been performed using a genetic model (autosomal dominant, f = 0.72, q = 0.02, phenocopies = 0.001) as described in Kennedy et al., 1988. Analyses of the restriction fragment length polymorphism (RFLP), allele-specific oligonucleotides (ASO), and short tandem repeat (STR also called microsatellite) data for 180 polymorphisms (individual probe-enzyme, ASO, or STR systems) at 155 loci have been completed using the MLINK and LIPED programs. Linkage to schizophrenia was excluded, under the given model, at 47 loci; indeterminate lod scores occurred at 108 loci. The total exclusion region across 20 chromosomes is estimated at 330 cM; 211 cM excluded by pairwise analyses and 119 cM previously excluded by multipoint analyses (Kennedy et al., 1989: Schizophr Bull 15:383-391; Moises et al. 1991: Genet Epidemiol 2:99-110; Hallmayer et al., 1992: Arch Gen Psychiatry 49:216-219).

Alleles↗
PubMed1994

Linkage study of a susceptibility locus for schizophrenia in the pseudoautosomal region.

Several lines of evidence suggest that the sex chromosomes have a role in the expression of schizophrenia. Gender differences in response to treatment, age at onset of illness, and prognosis indicate an influence of sex in differential expression of schizophrenia. On the basis of a higher-than-expected concordance for sex among siblings with schizophrenia, as well as the findings of cytogenetic abnormalities of the sex chromosomes in some schizophrenia patients, a pseudoautosomal location for a schizophrenia susceptibility locus has been proposed. To test this hypothesis, we investigated genetic linkage of the pseudoautosomal region to schizophrenia in a large Swedish kindred. Using pairwise analyses we tested eight markers spanning the most telomeric region to the boundary of the sex-specific region. In addition, we used multi-point analysis with five markers spanning the region to test for the presence of a schizophrenia susceptibility locus in the pseudoautosomal region. No evidence was found for linkage to schizophrenia under the given genetic model: "autosomal" dominant, f (penetrance) = 0.72, q (gene frequency) = 0.02, phenocopies = 0.001.

Chromosome Aberrations↗
PubMed1993

Physical and genetic maps for chromosome 10.

A fluorescence in situ hybridization (FISH) physical map of 14 polymorphic loci on chromosome 10 covers over 62% of the fractional length of chromosome 10. The positions of three previously mapped loci are confirmed, nine more are refined, and two new loci are cytogenetically mapped. The order of loci determined by FISH agrees with that obtained by genetic linkage studies. When the distance estimates for the physical map are compared to the distance estimates of our existing linkage map, the sex average ratio of the fractional length (FL) per centimorgan (cM) for this portion of chromosome 10 is 0.004 (or 0.4% FL/cM). However, the average ratios for male- and female-specific genetic distances are quite different, in agreement with an overall higher rate of recombination in females (0.008 FL/cM and 0.003 FL/cM, respectively). Moreover, the ratio across the centromere is larger for both the male (0.031 FL/cM) and the female (0.009 FL/cM) than the ratio encompassing the q arm (0.006 FL/cM for males and 0.002 FL/cM for females), suggesting that there is reduced recombination at the centromere in both the male and the female maps when compared to the physical distance generated from FISH on metaphase chromosomes.

Chromosome Mapping↗