Human GABA(B) receptor 1 gene: eight novel sequence variants.

GABA (gamma-aminobutyric acid) is the principal inhibitory neurotransmitter in the brain. The human GABA(B) receptor (GABBR1) maps to the human leukocyte antigen (HLA) region of chromosome 6. Its function and location in a susceptibility region for schizophrenia, epilepsy, and dyslexia make GABBR1 a candidate gene for neurobehavioral disorders. We report the characterization of GABBR1 gene mutations in 100 chromosomes from a mixed American population. Eleven distinct mutations were found, including two previously reported missense mutations (A20V and G489S) and a previously reported silent 1977 T>C transition. Here, we report four novel silent substitutions (39C>T, 1473T>C, 1476T>C, 1545T>C) and four novel intron variants. These DNA variants may be useful in association and linkage studies of neurobehavioral disorders, and in pharmacogenetic studies of drugs targeting GABBR1.

Linkage studies suggest a possible locus for developmental dyslexia on chromosome 1p.

Eight extended dyslexic families with at least four affected individuals were genotyped with twelve genetic markers spanning the Rh (rhesus factor) locus. Eleven of these markers were located on the short arm and the other was on the long arm of chromosome 1. Five theoretically derived phenotypes were used in the linkage analyses: 1) phonemic awareness; 2) phonological decoding; 3) rapid automatized naming; 4) single word reading; and 5) vocabulary. In addition, a lifetime diagnosis of dyslexia was used as a phenotype. Both parametric and non-parametric genetic analyses were completed. The results supported the importance of a putative locus on 1p. In addition, two-locus analyses assuming the interaction between a 1p locus and a 6p locus, previously shown to be of interest for dyslexia, were conducted. As a result, the nonparametric linkage (NPL) scores for rapid automatized naming and phonological decoding were significantly increased. In particular, the NPL scores for rapid automatized naming exceeded 5.0 for certain markers. These results provide strong evidence for separate but jointly acting contributions of the 1p and 6p loci to the reading impairments associated with rapid naming and suggestive evidence for a similar mechanism involving phonological decoding.

Long-term effects of HIV counseling and testing for women: behavioral and psychological consequences are limited at 18 months posttest.

Behavioral and psychological consequences of HIV counseling and testing (HIV C&T) for women were examined in a longitudinal, prospective study. Women who received HIV C&T at community health clinics (n = 106) and a comparison group of never-tested women (n = 54) were interviewed five times over 18 months. There was no change in risk behaviors as a consequence of testing: tested and untested women engaged in high-risk sexual behavior at baseline and 18 months later. Tested women reported more anxiety, depression, and intrusive thoughts about AIDS than did untested women. Although tested women were more concerned about AIDS, their potential risk factors over the study period generally were equivalent to those for untested women. HIV counseling and testing should be considered one aspect of a broader program of HIV prevention. Identification of alternative interventions must be a public health priority.

Unified psychology.

The authors describe an approach to psychology they refer to as unified psychology, which is the multiparadigmatic, multidisciplinary, and integrated study of psychological phenomena through converging operations. In this article, they unpack this definition and explore some of its implications. First, they review some previous efforts to conceive of a unified psychology and consider objections to such an undertaking. Second, they discuss the importance of converging operations for psychology. Third, they consider the need for multidisciplinary and integrated study of psychological phenomena that focuses on the phenomena rather than on particular lines of disciplinary inquiry. Fourth, they ponder the problem of investigators' becoming locked into a single paradigm with its attendant set of presuppositions about psychological theory and research. Fifth, they outline some possible objections to their proposal and respond to them. Finally, they discuss some implications of their views.

A Russian adaptation of the Child Behavior Checklist: psychometric properties and associations with child and maternal affective symptomatology and family function.

The Child Behavior Checklist's (CBCL) applicability to a sample of 105 Russian 9- and 10-year-old children was evaluated by examining the internal consistency of Russian adaptations of parent and teacher report forms. In addition, child behavior scores were correlated with child report of internalizing symptoms and maternal reports of their own internalizing symptoms and general family functioning. Finally, rates of child behavior problems and patterns of interrater agreement were compared with U.S. normative data. The psychometric properties of the adaptations demonstrate the adequacy of these instruments for use in Russia. Internal consistency and interrater agreement were generally comparable to estimates obtained in U.S. normative samples. Further, an exploration of the construct validity of the Russian versions of the CBCL and Teacher Report Form (TRF) lends additional support to the adequacy of these instrument.

Russian "defectology": anticipating Perestroika in the field.

Created as a part of the general Russian educational system, special education in Russia has mirrored all the good and bad qualities of that system. It was during the Soviet phase of its existence that Russian remedial education developed its specific and unique character, reflecting the structure and values of the global social environment. Despite the fact that Russian society realized the need to change its general educational system, remedial education remained untouched by reconstructive forces. This article discusses both the background and the current state of treatment of children with disabilities in Russia. The theoretical basis of the modern Russian approach to disability, the current needy population, and the existing system for referral and rehabilitation are described, and emerging trends and new perspectives on the Russian treatment of children with disabilities are presented.

Emerging issues in the genetics of dyslexia: a methodological preview.

A review of the classic and recent evidence on the genetics of reading disability (RD) shows encouraging progress, and accumulating evidence of genetic risk factors that operate within families and are separately localizable to more than one chromosomal region. The accelerating pace of these findings, however, suggests the need to consider some methodological issues about the design and interpretation of current and future studies. A major issue is the shape of the distribution of reading ability in the population, and we offer three tests of increasing rigor for determining whether those distributions are categorical, and hence not suitable for analyses that depend on the assumption of a continuous normal distribution. These tests are as follows: a nonnormal preponderance of cases with RD (i.e., the hump in the lower end of the distribution); a difference in the within-group variance-covariance matrices for typical readers compared to those with RD; and a correlation between a neurogenetically relevant criterion and a categorical reading variable that is larger than the correlation between the same criterion and a continuous version of the same reading variable. We emphasize also the importance of interactive relationships between multiple genetic loci, the variations in genotypic range as well as type of affectedness, the need to account for remediation variance, and the importance of lifespan changes in the phenotypes.

[Dynamics of the haplotype frequencies in populations: study using the Monte Carlo method]. / Dinamika chastot gaplotipov v populiatsiiakh: issledovanie metodom Monte Karlo.

A program that simulates random genetic drift, random mating, recombination, natural selection, and mutation process was developed to study the influence of these processes on the evolutionary dynamics of haplotype frequencies in populations. The program can track nine sites, each including up to 15 alleles. The program application was illustrated by the study of frequency dynamics in the HOXB haplotypes (17q) in different populations. The simulation results confirmed the hypothesis, which was proposed on the basis of the experimental data, that, in the absence of recurrent mutations, population mixing, and natural selection, the harmonic mean of the effective population size from the moment of New World colonization up to now was more than 1000.

BDNF Val66Met and cognition: all, none, or some? A meta-analysis of the genetic association.

The Val66Met, G196A (rs6265) polymorphism in the brain-derived neurotrophic factor gene, BDNF, located at 11p13, has been associated with a wide range of cognitive functions. Yet, the pattern of results is complex and conflicting. In this study, we conducted a meta-analysis that included 23 publications containing 31 independent samples comprised of 7095 individuals. The phenotypes that were examined in this analysis covered a wide variety of cognitive functions and included indicators of general cognitive ability, memory, executive function, visual processing skills and cognitive fluency. The meta-analysis did not establish significant genetic associations between the Val66Met polymorphism and any of the phenotypes that were included.

Autism and the serotonin transporter: the long and short of it.

Autism is a neurodevelopmental disorder manifesting early in childhood. Some symptoms of autism are alleviated by treatment with selective serotonin reuptake inhibitors, which are known to interact with the serotonin transporter. Moreover, variation in the gene that encodes the transporter (SLC6A4), especially the HTTLPR locus, is known to modulate its expression. It is natural, therefore, to evaluate whether this variation plays a role in liability to autism. We investigated the impact of alleles at HTTLPR and three other loci in SLC6A4 by using a large, independent family-based sample (390 families, 1528 individuals) from the NIH Collaborative Programs of Excellence in Autism (CPEA) network. Allele transmissions to individuals diagnosed with autism were biased only for HTTLPR, both for the narrow diagnosis of autism (P=0.035) and for the broader diagnosis of autism spectrum (P=0.007). The short allele of HTTLPR was significantly overtransmitted. Investigation of haplotype transmissions suggested that, in our data, biased transmission was only due to HTTLPR. With respect to this locus, there are now seven of 12 studies reporting significant transmission bias of HTTLPR alleles, a noteworthy result in itself. However, the studies with significant findings are almost equally divided between overtransmission of short and overtransmission of long alleles. We place our results within this extremely heterogeneous field of studies. Determining the factors influencing the relationship between autism phenotypes and HTTLPR variation, as well as other loci in SLC6A4, could be an important advance in our understanding of this complex disorder.

Developmental dyslexia: an update on genes, brains, and environments.

The science of reading and developmental dyslexia has experienced spectacular advances during the last few years. Five aspects of this research are discussed in the article. (1) The holistic phenomenon of reading is complex. Many lower-level psychological processes (e.g., phonemic awareness, phonological decoding, ability to process stimuli rapidly and automatize this process, memory, ability to recognize words) contribute to a single act of reading. Conceptualizing the complex process of reading through its partly overlapping but partly independent components--which contribute to, but do not fully explain, the holistic process of reading--provides an excellent model for understanding complex hierarchies of higher mental functions. Those who master reading skills successfully and those who have difficulties doing so differ in a wide range of reading-related processes. The central deficit experienced by poor readers appears to be related to phonological processing (a complex hierarchy of functions related to processing phonemes), whereas characteristics of automatization processes seem to moderate the reading outcome for people whose phonological skills are weak. (2) There are new data addressing models of dyslexia in languages other than English. The most fascinating finding is that the model implicating phonological deficit as central to dyslexia, and the lack of ability to automatize as leading to troubled reading, appears to be universal, regardless of the specific language. However, there is an interaction effect between the characteristics of a particular language and the developmental model of dyslexia. In phonologically more difficult languages (e.g., English), the most pronounced weakness appears to occur in phonological processing, whereas in phonologically easier languages (e.g., German), the crucial role in the manifestation of dyslexia is played by the lack of the skills needed to achieve automatization. (3) There is abundant evidence that reading (i.e., any single act of reading as well as reading as a holistic process) is "cooked" by the brain. Although no unified brain map of reading has been developed, some specific areas of the brain have been implicated in different reading-related cognitive processes by different laboratories and on different samples. (4) Indisputable evidence has been accumulated suggesting the involvement of the genome in developmental dyslexia. As of now, specific regions of the genome have been identified as being intimately involved with a number of different reading-related processes. Today the field of developmental dyslexia is the only area of genetic studies of human abilities and disabilities in which linkages to the genome have been robustly replicated in independent laboratories. (5) Finally, evidence suggests that developmental dyslexia might be only one of the manifestations of a deep, underlying, anatomical syndrome. The comorbidity of developmental dyslexia with both internalizing and externalizing behavioral disturbances, as well as with other learning disabilities, underscores the need for wide-ranging cognitive and behavioral approaches in the remediation programs offered to dyslexic children.

An extension of affected-pedigree-member analyses to triads of relatives.

The affected third-degree relatives method ("cousins method"-CM) shares key features with the affected-sibling method, but it groups first cousins in triads, with the hope of requiring fewer individuals to be typed. The aim is to provide an efficient and computationally convenient method of genome screening, capitalizing on the vast number of highly informative markers mapped in recent years. The nonparametric CM statistic measures increased marker similarity, making no assumptions concerning how the disease is inherited; this can be advantageous when dealing with complex diseases for which the mode of inheritance is difficult to determine. This article presents a brief statistical development of the CM method and describes the results of applying the method to one replicate of the simulated extended family data set.

Similarity in general cognitive ability, creativity, and cognitive style in a sample of adolescent Russian twins.

Data on five tests of general and specific cognitive abilities, cognitive styles, and creativity, obtained from members of 60 identical and 63 fraternal Russian adolescent twin pairs, are presented. All tests are adaptations of standardized instruments widely used outside of the Soviet Union. Identical and fraternal twin correlations for general cognitive ability yielded a lower estimate of heritability (0.29) than generally found in other countries worldwide (0.52) although the twin correlations themselves are fairly comparable to figures from other countries and cultures--0.83 and 0.69 for Russian identical and fraternal twin pairs, respectively, vs 0.86 and 0.60 for non-Russian identical, and fraternal twin pairs. Twin correlations for other cognitive-related abilities assessed were also comparable to correlations obtained outside the Soviet Union with the exception of creativity which yielded higher within-pair resemblance than reported in previous twin studies.

Haplotype evolution and linkage disequilibrium: A simulation study.

We simulated the evolution of a three-site haplotype system, two restriction fragment length polymorphisms flanking one short tandem repeat polymorphism, under five different demographic scenarios, three with constant population size and two with population growth. The simulation was designed to observe the effects of population history, recombination fraction, and mutation rate on allele and haplotype frequencies, haplotype diversity, frequency of ancestral alleles, and linkage disequilibrium. The known ancestral haplotypes were often found at low frequencies and even became extinct after 5, 000 generations, especially with small effective population sizes. The original linkage disequilibrium was eroded and even reversed.

Chromosome 6p influences on different dyslexia-related cognitive processes: further confirmation.

In this study, which is a continuation and an extension of an earlier study, we enrolled two new families (N=31) and recruited more individuals from the previously ascertained families (N=56). The eight multiplex families (N=171) presented in this study were ascertained from a sample of adult probands whose childhood reading history is well documented through archival information. Six phenotypes were constructed to span a range of dyslexia-related cognitive processes. These phenotypes were (1) phonemic awareness (of spoken words); (2) phonological decoding (of printed nonwords); (3) rapid automatized naming (of colored squares or object drawings); (4) single-word reading (orally, of printed real words); (5) vocabulary; and (6) spelling (of dictated words). In addition, the diagnosis of lifelong dyslexia was established by clinical means. Genotyping was done with nine highly polymorphic markers from the 6p22.3-6p21.3 region. The results of two- and multipoint identity-by-descent and identity-by-state analyses supported the importance of a putative locus in the D6S464-D6S273 region for a number of dyslexia-related cognitive deficits.

Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15.

Six extended dyslexic families with at least four affected individuals were genotyped with markers in three chromosomal regions: 6p23-p21.3, 15pter-qter, and 16pter-qter. Five theoretically derived phenotypes were used in the linkage analyses: (1) phonological awareness; (2) phonological decoding; (3) rapid automatized naming; (4) single-word reading; and (5) discrepancy between intelligence and reading performance, an empirically derived, commonly used phenotype. Two-point and multipoint allele-sharing analyses of chromosome 6 markers revealed significant evidence (P < 10(-6)) for linkage of the phonological awareness phenotype to five adjacent markers (D6S109, D6S461, D6S299, D6S464, and D6S306). The least compelling results were obtained with single-word reading. In contrast, with chromosome 15 markers, a LOD score of 3.15 was obtained for marker D15S143 at theta = 0.0 with single-word reading. Multipoint analyses with markers adjacent to D15S143 (D15S126, D15S132, D15S214, and D15S128) were positive, but none reached acceptable significance levels. Chromosome 15 analyses with the phonological awareness phenotype were negative. Parametric and nonparametric linkage analyses with chromosome 16 markers were negative. The most intriguing aspect of the current findings is that two very distinct reading-related phenotypes, reflecting different levels in the hierarchy of reading-related skills, each contributing to different processes, appear to be linked to two different chromosomal regions.

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.