Lori Crawford

A Genomewide Scan for Loci Involved in Attention-Deficit/Hyperactivity Disorder

Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs.

Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder. Evidence from twin, adoption, and family studies provide support for a genetic contribution to the etiology of ADHD. Several candidate gene studies have identified an association between a 7-repeat variant in exon 3 of the dopamine 4 receptor gene (DRD4) and ADHD. However, in spite of the positive reports finding association of the exon 3 VNTR with ADHD, several other polymorphisms within DRD4 have been identified that conceivably could contribute to risk for ADHD. Recently, another common polymorphism of the DRD4 gene has been described involving a 120-bp repeat element upstream of the 5′ transcription initiation site. In this report, we describe results of analysis of the DRD4 120-bp repeat promoter polymorphism in a sample of 371 children with ADHD and their parents, using the transmission disequilibrium test (TDT). Results showed a significant preferential transmission of the 240-bp (long) allele with ADHD. Exploratory analyses of the Inattentive phenotypic subtype of ADHD strengthened the evidence for linkage. These data add further support for the role of DRD4 variants conferring increased risk for ADHD, and imply that additional studies of DRD4 and other related genes are needed.

Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop ADHD. Reports implicate variants of genes important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5. In the present study, we genotyped a large multiplex sample of ADHD affected children and their parents for polymorphisms in genes previously reported to be associated with ADHD. Associations were tested by the transmission disequilibrium test (TDT). The sample is sufficient to detect genotype relative risks (GRRs) for putative risk alleles. The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed a significant bias in transmission of the insertion (χ2=7.58, P=0.006) as suggested by an analysis of a subset of these families. The seven repeat allele of the DRD4 48-bp repeat polymorphism (DRD4.7) was not significantly associated with ADHD in the large sample in contrast to our earlier findings in a smaller subset. We replicate an association of a dinucleotide repeat polymorphism near the DRD5 gene with ADHD by showing biased nontransmission of the 146-bp allele (P=0.02) and a trend toward excess transmission of the 148-bp allele (P=0.053). No evidence for an association was found for polymorphisms in DRD2 or DAT1 in this sample. The DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing a significant association in this large sample of predominantly multiplex families with ADHD, with estimated GRRs of 1.7 and 1.37, respectively.

Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism

BACKGROUND The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.

Work environment and occupational health of dental hygienists: a qualitative assessment.

Objective: We sought to characterize the work environment and identify factors that influence the occupational health of dental hygienists. Methods: We conducted a qualitative analysis of dental hygiene work based on five national focus groups. Results: We found that musculoskeletal symptoms are common, particularly after 10 years; common ergonomic problems included instruments and chairs. Important nonphysical workplace problems include role ambiguity (eg, employee vs. independent practitioner), inadequate recognition, role identity (eg, distinction from dental assistants), role conflict (eg, with dentists and spousal office managers), and social isolation. Conclusions: Work organizational factors (eg, frequent part-time work, inadequate breaks, perception as a “second team” distinct from the dentist and dental-assistant team) impede the remediation of ergonomics and other problems. Job flexibility encourages hygienists to change work hours or location rather than deal with work conditions. Occupational health interventions should address social environment and work organization.

Work environment of dental hygienists

Objective: We sought to evaluate how musculoskeletal disorders and workplace psychosocial factors affect dental hygienists’ work hours and productivity. Methods: We mailed a survey to dental hygienists in Los Angeles and Orange Counties, California. Results: Musculoskeletal pain caused 27% of hygienists to decrease work hours and 8.7% to change office locations. Hand/wrist pain caused the most missed workdays. Conversely, conflicts with the dentist caused 28.2% of dental hygienists to change jobs and 12.7% to decrease work hours. Conflicts with staff caused 17.1% to change office locations but only 7.0% to decrease work hours. This pattern was confirmed with multiple logistic regression analyses. Conclusions: Musculoskeletal and psychosocial factors affect dental hygienists differently: musculoskeletal discomfort is more likely to cause dental hygienists to decrease their working hours, whereas professional and social conflicts are more likely to lead to change in work location.

Formaldehyde Exposure and Mortality Risks From Acute Myeloid Leukemia and Other Lymphohematopoietic Malignancies in the US National Cancer Institute Cohort Study of Workers in Formaldehyde Industries

Objectives: To evaluate associations between cumulative and peak formaldehyde exposure and mortality from acute myeloid leukemia (AML) and other lymphohematopoietic malignancies. Methods: Cox proportional hazards analyses. Results: Acute myeloid leukemia was unrelated to cumulative exposure. Hodgkin lymphoma relative risk estimates in the highest exposure categories of cumulative and peak exposures were, respectively, 3.76 (Ptrend = 0.05) and 5.13 (Ptrend = 0.003). There were suggestive associations with peak exposure observed for chronic myeloid leukemia, albeit based on very small numbers. No other lymphohematopoietic malignancy was associated with either chronic or peak exposure. Conclusions: Insofar as there is no prior epidemiologic evidence supporting associations between formaldehyde and either Hodgkin leukemia or chronic myeloid leukemia, any causal interpretations of the observed risk patterns are at most tentative. Findings from this re-analysis do not support the hypothesis that formaldehyde is a cause of AML.

Computer algorithm for automated work group classification from free text : The DREAM technique

Objective: This study developed and tested a computer method to automatically assign subjects to aggregate work groups based on their free text work descriptions. Methods: The Double Root Extended Automated Matcher (DREAM) algorithm classifies individuals based on pairs of subjects’ free text word roots in common with those of standard classification systems and several explicitly defined linkages between term roots and aggregates. Results: DREAM effectively analyzed free text from 5887 participants in a multisite chronic obstructive pulmonary disease prevention study (Lung Health Study). For a test set of 533 cases, DREAMs classifications compared favorably with those of a four-human panel. The humans rated the accuracy of DREAM as good or better in 80% of the test cases. Conclusions: Automated text interpretation is a promising tool for analyzing large data sets for applications in data mining, research, and surveillance. Work descriptive information is most useful when it can link an individual to aggregate entities that have occupational health relevance. Determining the appropriate group requires considerable expertise. This article describes a new method for making such assignments using a computer algorithm to reduce dependence on the limited number of occupational health experts. In addition, computer algorithms foster consistency of assignments.

Working words: real-life lexicon of North American workers.

Objective: This study describes a new computer methodology for analyzing workers’ free text work descriptions. Methods: Computerized lexical analysis was applied to work descriptions of participants in the Lung Health Study, a smoking-cessation study in persons with early chronic obstructive pulmonary disease. Text was parsed and analyzed as single term roots and pairs of roots commonly occurring together. Results: The frequencies of terms reflect the work of a population; our subjects’ most frequently used terms included “sale, office, service, business, engine[er], secretary, construct, driv[e], comput[e], teach, truck.” Standard classification schemes (NAICS and SOC) and textbooks use terms inconsistent with those of actual workers. Many common empirical terms imply both industry and job information content, although traditional coding schemes separate industry and job title. Conclusions: Formal analyses of language may facilitate communication, identify translation priorities, and allow automated work coding.