Biomedical subjects

D L Pauls

Publications and source records attributed to D L Pauls.

At least 19 recordsLinked to original sources

PubMed2003

A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q.

A genome scan was performed on 164 Dutch affected sib pairs (ASPs) with attention-deficit/hyperactivity disorder (ADHD). All subjects were white and of Dutch descent and were phenotyped according to criteria set out in the Diagnostic and Statistical Manual Of Mental Disorders, 4th edition. Initially, a narrow phenotype was defined, in which all the sib pairs met the full ADHD criteria (117 ASPs). In a broad phenotype, additional sib pairs were included, in which one child had an autistic-spectrum disorder but also met the full ADHD criteria (164 ASPs). A set of 402 polymorphic microsatellite markers with an average intermarker distance of 10 cM was genotyped and analyzed using the Mapmaker/sibs program. Regions with multipoint maximum likelihood scores (MLSs) >1.5 in both phenotypes were fine mapped with additional markers. This genome scan indicated several regions of interest, two of which showed suggestive evidence for linkage. The most promising chromosome region was located at 15q, with an MLS of 3.54 under the broad phenotype definition. This region was previously implicated in reading disability and autism. In addition, MLSs of 3.04 and 2.05 were found for chromosome regions 7p and 9q in the narrow phenotype. Except for a region on chromosome 5, no overlap was found with regions mentioned in the only other independent genome scan in ADHD reported to date.

Adolescent↗

PubMed2003

A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan.

We conducted a 10 centimorgan (cM) linkage genome scan in a set of American extended pedigrees ascertained through probands with panic disorder. Several anxiety disorders segregate in these families. In this article, we describe results for simple phobia from 14 of these families (including 129 subjects of whom 57 are affected). A total of 422 markers were genotyped. Multipoint lod score analyses (fully parametric and simple parametric models) and nonparametric analyses were completed using ALLEGRO. We observed significant linkage of simple phobia to chromosome 14 markers. The highest lod score under a fully parametric model was 3.17, at marker D14S75, under a dominant model. Under a fully parametric recessive model, the maximum lod score, also at D14S75, was 2.86. Analysis under a simple parametric model resulted in lod scores of 3.70 (dominant model) or 3.30 (recessive model). The highest Zlr score observed was 3.93 (P = 4.1 x 10(-5)). The Zlr score was >1 for an extensive region, >77 cM. In all, 12 of the 14 families studied provided positive or zero lod scores at marker D14S75 (dominant model). The homologous genomic region has been implicated by studies mapping quantitative trait loci for a mouse model of fear. The linkage peak may be regarded as highly promising, owing to the breadth of the peak, the convergence of results under different models of inheritance and different analysis methods, and the support from an animal model. This is the first genome scan linkage study for simple phobia, a common disorder that causes high morbidity in the US population.

Anxiety↗

PubMed2001

Linkage genome scan for loci predisposing to panic disorder or agoraphobia.

We conducted a 10 cM linkage genome scan in a set of 20 American pedigrees (153 subjects), ascertained through probands with panic disorder (PD). Several anxiety disorders segregate in these families; they were diagnosed on the basis of Schedule for Affective Disorders and Schizophrenia interview. In this article, we describe results for panic disorder and agoraphobia, which are closely related, common, heritable anxiety disorders. This is the first complete linkage genome scan for agoraphobia and the third for PD. A total of 407 markers (389 autosomal, 18 X chromosome) were genotyped. Multipoint LOD score and NPL analysis were completed using GENEHUNTER2. For PD, two genomic regions meet criteria for suggestive linkage. One of these regions is on chromosome 1 (LOD score = 2.04). This region coincides with a region that generated a LOD score of 1.1 in a previous genome scan by Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. The other (LOD score = 2.01) is located on chromosome 11p and occurs at marker CCKBR, one of eight candidate genes examined. For agoraphobia, the most promising potential linkage was on chromosome 3 (NPL score = 2.75; P = 0.005). This was accounted for primarily by a single family that by itself generated an NPL score of 10.01 (P = 0.0039) and a LOD score of 2.10. These results provide initial evidence for a genetic locus on chromosome 3 that contributes to risk for agoraphobia. They also support suggestive linkage to two risk loci for panic disorder. Additional potential loci were identified with lesser statistical support; several of these were consistent with previously reported panic disorder linkage results. Overall, the results presented here suggest that PD and agoraphobia are complex traits that share some, but not all, of their susceptibility loci. Published 2001 Wiley-Liss, Inc.

Agoraphobia↗

PubMed2001

Case control and family-based studies of tryptophan hydroxylase gene A218C polymorphism and suicidality in adolescents.

The association of suicidality with polymorphism A218C in intron 7 of tryptophan hydroxylase (TPH) gene remains controversial. The aim of this study was to use family-based methods to examine this association in adolescents in order to eliminate the difficulty of sampling a control group from the same ethnic population. Eighty-eight inpatient adolescents who recently attempted suicide were assessed by structured interview for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, aggression, and depression. DNA samples were collected from all subjects, from both biological parents of 40 subjects and from one parent of 9 subjects; TPH allele frequencies were calculated and tested for association to phenotype, stratified by severity, using the haplotype relative risk (HRR) and transmission disequilibrium test (TDT) methods (n = 49). The frequencies were also compared for all the Jewish subjects (n = 84) to the known frequencies of these alleles in healthy Jewish populations. There was no significant allelic association of A218C polymorphism with suicidal behavior or other phenotypic measures according to the HRR method (chi-square = 0.094; P = 0.76), the TDT (chi-square = 0.258; P = 0.61), or association analysis to known population frequencies (chi-square = 1.667, P = 0.19 for Ashkenazi, and chi-square = 0.810, P = 0.37 for non-Ashkenazi). Analysis of variance with the Scheffè test demonstrated a significant difference between CC and AA genotypes in suicide risk and depression among the patients (n = 88). The findings suggest that polymorphism A218C has no major relevance to the pathogenesis of adolescent suicidal behavior, but may have a subtle effect on some related phenotypes.

Adolescent↗

PubMed2001

A family study of Tourette syndrome in Japan.

Although the mode of inheritance remains in doubt, twin and family studies conducted mostly in the United States and western Europe suggest that genetic factors play an important role in the transmission and expression of Tourette syndrome (TS). In an effort to evaluate population-based genetic differences, we generated risk estimates for first-degree relatives of TS probands in Japan using methods similar to those utilized in recent Western studies. The subjects were 52 TS probands seen at an outpatient clinic of Tokyo University Hospital and their 165 first-degree relatives. All probands and one or more first-degree relatives in each family were interviewed concerning the presence of tic and obsessive-compulsive symptoms by expert clinicians. The age-corrected rates of TS, chronic motor tics, obsessive-compulsive disorder, and subclinical obsessive-compulsive symptoms in the first-degree relatives were 2.0%, 12.0%, 1.6%, and 7.0%, respectively. Rates of TS and related disorders in Japan appear to be much lower than those in recent Western family studies. If replicated, these data suggest that there may be differences in the nature and frequency of vulnerable alleles for TS and related disorders in the Japanese compared to European populations.

Adolescent↗

PubMed2001

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.

Adolescent↗

PubMed2001

Symptom dimensions in obsessive-compulsive disorder: toward quantitative phenotypes.

The authors review evidence of symptom dimensions in obsessive-compulsive disorder (OCD) and their potential value as quantitative phenotypes in genetic studies of OCD and related conditions. Preliminary evidence supports the existence of four separate symptom dimensions. A small series of clinical and family genetic studies support the validity of one or more of these dimensions. However, critical data concerning the distribution of these dimensions in the general population are lacking, and the hereditability of these traits has yet to be established.

Genetic Testing↗

PubMed2001

The genetics of Tourette syndrome.

Twin and family studies demonstrate that Tourette syndrome (TS) is a genetic disorder. Early segregation analyses of family data were consistent with the hypothesis of autosomal dominant transmission; however, more recent studies suggest that the mode of inheritance is more complex. Current findings suggest that there are genes of major effect with other genes acting as modifiers. Several genome scans have been completed and several regions of interest have been identified that may harbor susceptibility genes for TS. Work is currently underway to replicate and extend these initial results.

Family Health↗

PubMed2001

Tourette's syndrome and related disorders.

The past two decades of research have demonstrated that Tourette's syndrome (TS) is likely to be more genetically heterogeneous than initially appreciated. Nonetheless, important progress toward the understanding of genetic influences in TS has been made by the combination of family and twin studies, segregation analyses, parametric and nonparametric linkage analyses, and association studies. The identification of genetic factors involved in TS will have important implications for clinical research. Once it is possible to stratify patients meaningfully with respect to known genetic markers, a reassessment of diagnostic nosology, neuroimaging findings, psychopharmacology, and disease course will be possible. Another result of gene identification will be the rapid clarification of additional environmental factors influencing the development of the disorder. Because it may be easier to influence the environment and behavior rather than to change genes, exploration of such gene-environment interactions may lead to the most significant clinical contributions in the near term.

Adolescent↗

PubMed2001

Update on the genetics of Tourette syndrome.

There has been significant progress in the understanding of the genetics of TS since the last international symposium. At the present time, we stand at the threshold of identifying the regions harboring the genes important in the manifestation of this syndrome. The localization and characterization of genes important for the expression of the TS phenotype will be a major advance in our understanding of the pathogenesis of this disorder and will also provide a model for the study of other developmental disorders. Unquestionably, the replication of these initial linkage findings and the localization and characterization of genes responsible for the expression of TS and related disorders will be a major step forward in our understanding of the genetic/biologic risk factors important for the expression of these disorders. Furthermore, once genes conferring susceptibility to TS and associated behaviors have been characterized, further work will allow the identification of additional nongenetic factors that are important for the manifestation or the amelioration of the symptoms of the disorders (84). As discussed by Kidd (85) and Pauls (84), the identification of a linked marker will permit the design of much more incisive studies to illuminate the physiological/biochemical etiology of TS by examination of the gene product and its impact on the development of the disorders. On the other hand, by controlling for genetic factors, through the genetic case-control research paradigm (85), it will be possible to document more carefully the environmental/nongenetic factors important for the expression of TS and other disorders.

Genetic Linkage↗

PubMed2000

Genetic aspects of obsessive-compulsive disorder.

Developments in molecular genetic methods have proved to be powerful tools in the search for genes involved in complex diseases, and they hold the promise of understanding the genetic basis of OCD. The next step in understanding the genetics of OCD is the localization and characterization of the genes that confer susceptibility. A more complete understanding of the genetic basis of OCD and of the interactions between relevant genotypes and relevant environmental factors is important for clarification of the cause, pathogenesis, and treatment of this complex disorder. These genetic methods must be combined with careful clinical and epidemiologic work to correctly elucidate the cause of OCD. Future research also should define subsets of endophenotypes of the disorder. Factors such as neuropsychological functioning, personality testing, comorbidity, and age of onset are extremely useful in the continued study of genetic mechanisms involved in the cause of OCD.

Alleles↗

PubMed2000

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.

Adolescent↗

PubMed2000

The genetics of childhood psychiatric disorders: a decade of progress.

OBJECTIVE: To review the literature over the past decade on the genetics of childhood neuropsychiatric disorders. METHOD: A computerized search was performed for articles published in the past decade, and selected papers were highlighted. RESULTS: The past decade of research has illuminated the complex genetics of early-onset mental disorders. Advances in statistical methodologies and laboratory-based gene-hunting techniques are laying the foundation for a deeper understanding of both the biological and environmental factors that contribute to mental illness. Researchers are on the verge of identifying and characterizing genetic vulnerabilities involved in common childhood psychiatric syndromes. CONCLUSIONS: Although the study of the genetics of childhood psychiatric disorders has advanced significantly over the past decade, considerable work remains. The identification of genes conferring vulnerability to psychiatric illnesses will have the potential to transform the field by providing insight into both biological and environmental determinants that contribute to serious developmental and psychiatric disorders in children and adolescents. These advances promise new understanding and new avenues for prevention and treatment. They will also present physicians and families with significant clinical and ethical challenges.

Child↗

PubMed2000

Prodromal symptoms before onset of manic-depressive disorder suggested by first hospital admission histories.

OBJECTIVE: A priority for research on manic-depressive or bipolar I disorder (BPI) for children and adolescents has been to search for early predictors of the illness. METHOD: Medical record data were reviewed and systematically coded for a sample of 58 adult patients (32 males/26 females) with confirmed diagnoses of BPI to identify prodromal features and possible patterns of symptoms from the Amish Study. RESULTS: The most frequently reported symptoms included episodic changes in mood (depressed and irritable) and energy plus anger dyscontrol, with no significant gender differences. A progression of ages is seen for the most commonly reported symptoms prior to age 16. The time interval was 9 to 12 years between appearance of the first symptoms and onset of a documented BPI syndrome. CONCLUSIONS: The data suggest testable hypotheses about specific symptoms and behaviors that may be useful for the early detection of children at highest risk for developing manic-depressive disorder.

Adolescent↗

PubMed2000

Genetic studies of panic disorder: a review.

BACKGROUND: A review of the studies examining the genetic etiology of panic disorder shows the familial nature of the disorder and demonstrates that the etiology is greatly influenced by genetic factors. Strong evidence for vertical transmission in family studies led to molecular genetic studies, of which association designs appear promising, particularly when based on trait markers. DATA SOURCES: The MEDLINE and PsycLIT databases were searched for all reports published between 1966 and 2000 containing the keywords panic, genetic, twin, adoption, linkage, association, and QTL. CONCLUSION: We conclude that the multifactorial nature of panic disorder requires a multidisciplinary approach to gain insight into the determinants of the phenotype and the interaction of environmental and genetic factors.

Adoption↗

PubMed2000

Social and emotional adjustment in children affected with Gilles de la Tourette's syndrome: associations with ADHD and family functioning. Attention Deficit Hyperactivity Disorder.

This study examined social-emotional functioning in children with Gilles de la Tourette's syndrome (TS) alone and children with TS and Attention Deficit Hyperactivity Disorder (ADHD). In addition, the contribution of family functioning to social competence was examined. Children with a clinical diagnosis of TS were recruited from the Yale Child Study Center TS specialty clinic. Unaffected control children were recruited through newspaper advertisements and announcements within the university and at area schools. The final sample consisted of 72 children (45 boys and 27 girls) between the ages of 8 and 14. Sixteen children met DMS-III-R criteria for TS, 33 children met criteria for TS and ADHD, and 23 children had no psychiatric diagnoses. Children with TS and ADHD evidenced more externalizing and internalizing behavior problems and poorer social adaptation than children with TS only or unaffected controls. Children with TS only were not significantly different from unaffected controls on most measures of externalizing behaviors and social adaptation but did exhibit more internalizing symptoms. Tic symptom severity was not associated with social, behavioral, or emotional functioning among children with TS, even after stratifying by medication status. However, ADHD diagnosis, obsessional symptom severity, and family functioning were significantly associated with social and emotional adjustment among TS children. Moreover, family functioning was associated with social and emotional adjustment even after controlling for TS and ADHD diagnostic status. These findings demonstrate that much of the social and behavioral dysfunction in children with TS is ADHD-specific and children with TS alone have a very different social-emotional profile than do those with TS plus ADHD. Finally, social-emotional adjustment in children with TS is best understood within the family context.

Adaptation, Psychological↗

PubMed2000

Genetics and violence.

As is evident from this brief review, the genetic study of violence is maturing at an ever-increasing rate; much more work is needed to examine specific molecular genetic markers and their associated phenotypes, particularly in subjects with juvenile onset. It is also becoming clear that more work is needed to help delineate the specific phenotypes that are being transmitted within families. It is unlikely that we will find a gene or genes that are both necessary and sufficient for the manifestation of aggression and violence. It is more likely that specific genes will be associated with discrete factors that either increase the risk for the expression of violence or that are components of the violent phenotype. Thus, in addition to continuing research that examines the role of specific genetic factors in the manifestation of violence, more work is needed that will help further develop the nosology of violence and related behaviors. As noted previously, an understanding of the inherited phenotype is critical in the study of any disorder. It is especially important in the study of complex behaviors such as violence in which there may be several behavioral components that comprise the complete diagnostic category.

Adult↗

PubMed1999

Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores.

Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder characterized by recurring obsessions or compulsions that cause significant distress to the patient or significantly interfere with the patient's normal home, work, or social activities [Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC: American Psychiatric Association, 1994]. Twin and family studies have suggested that OCD has a significant genetic component. We performed complex segregation analyses using POINTER with families ascertained through an OCD-affected proband. In an attempt to resolve the phenotypic heterogeneity observed among individuals with OCD these segregation analyses used four factor-analytic symptom dimensions to subset the family sample based upon probands' symptom factor scores. Analysis of the entire sample allowed rejection of only the no transmission model; that model was also rejected in all subsequent analyses. Limiting the analyses to families with at least one OCD-affected member in addition to the proband (the demonstrably familial form of OCD) allowed rejection of all models except the mixed model. Analyses limited to families of high-factor-3 (symmetry and ordering symptoms) probands led to rejection of the polygenic model, indicating the involvement of a major locus. Additionally, the relative risk of OCD or subclinical OCD was 1.7 for relatives of probands with a factor 3 score greater than zero compared with relatives of probands with a low factor score. The symptoms attributed to high factor 3 scores (symmetry and ordering) may constitute a genetically significant symptomatic subtype of OCD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:669-675, 1999.

Aging↗