Research to classrooms: a co-designed curriculum brings All of Us data to secondary schools.

OBJECTIVES: We describe new curriculum materials for engaging secondary school students in exploring the "big data" in the NIH All of Us Research Program's Public Data Browser and the co-design processes used to collaboratively develop the materials. We also describe the methods used to develop and validate assessment items for studying the efficacy of the materials for student learning as well as preliminary findings from these studies. MATERIALS AND METHODS: Secondary-level biology teachers from across the United States participated in a 2.5-day Co-design Summer Institute. After learning about the All of Us Research Program and its Data Browser, they collaboratively developed learning objectives and initial ideas for learning experiences related to exploring the Data Browser and big data. The Genetic Science Learning Center team at the University of Utah further developed the educators' ideas. Additional teachers and their students participated in classroom pilot studies to validate a 22-item instrument that assesses students' knowledge. Educators completed surveys about the materials and their experiences. RESULTS: The "Exploring Big Data with the All of Us Data Browser" curriculum module includes 3 data exploration guides that engage students in using the Data Browser, 3 related multimedia pieces, and teacher support materials. Pilot testing showed substantial growth in students' understanding of key big data concepts and research applications. DISCUSSION AND CONCLUSION: Our co-design process provides a model for educator engagement. The new curriculum module serves as a model for introducing secondary students to big data and precision medicine research by exploring diverse real-world datasets.

"What does it matter?" Young sexual minority men discuss their conversations with sexual partners about HPV vaccination.

Objective: Human papillomavirus vaccination coverage is suboptimal, especially among males. Social networks influence young adults' health behaviors and could be leveraged to promote vaccination. We sought to describe how young sexual minority men communicate about human papillomavirus (HPV) vaccination with their sexual partners. Participants: National (U.S.) sample of sexual minority men ages 18-26 (n = 42) from January 2019. Methods: We conducted four online focus groups and identified salient themes using inductive content analysis. Results: Across groups, participants described that HPV vaccination is not a focus of their conversations with sexual partners. Other key themes related to HPV vaccine communication included: varying discissions based on relationship type, and valuing conversations with partners about safer sex. Conclusions: Findings provide novel insight into how young sexual minority men communicate with their sexual partners about HPV vaccination and identify potential areas for interventions to promote communication. Future research is needed to investigate associations between partner communication and HPV vaccine uptake.

A Reasoned Action Approach to Depression Help-Seeking Messaging for College Students: Implications of Cognitive Biases in Depression.

In this study we integrated insights from research on cognitive biases in depression with the reasoned action approach to predicting and changing behavior (RAA) with the goal of identifying implications for help-seeking messaging for college students with varying levels of depression. Findings from a sample of 374 U.S. college students support the ability of RAA to explain help-seeking intentions for non-depressed, mildly depressed students, and moderate to severely depressed students. More severe depression was associated with less favorable attitudes, perceived norms, perceived capacity, and intention; changes in the relative strength of attitudes, perceived norms, and perceived capacity in explaining help-seeking intentions; stronger expectations of negative outcomes of help-seeking and weaker expectations of positive outcomes; and to some extent, stronger expectations of negative outcomes for oneself than for others. These findings underscore that depressed students construe help-seeking differently than non-depressed students, and that depressed and non-depressed students need different help-seeking messages.

Challenges related to human papillomavirus (HPV) vaccine uptake in Minnesota: clinician and stakeholder perspectives.

BACKGROUND: Human papillomavirus (HPV) vaccination rates among adolescents are increasing in Minnesota (MN) but remain below the Healthy People 2020 goal of 80% completion of the series. The goal of this study was to identify messaging and interventions impacting HPV vaccine uptake in MN through interviews with clinicians and key stakeholders. METHODS: We conducted semi-structured key participant interviews with providers and stakeholders involved in HPV vaccination efforts in MN between 2018 and 2019. Provider interview questions focused on messaging around the HPV vaccine and clinic-based strategies to impact HPV vaccine uptake. Stakeholder interview questions focused on barriers and facilitators at the organizational or state level, as well as initiatives and collaborations to increase HPV vaccination. Responses to interviews were recorded and transcribed. Thematic content analysis was used to identify themes from interviews. RESULTS: 14 clinicians and 13 stakeholders were interviewed. Identified themes were grouped into 2 major categories that dealt with messaging around the HPV vaccine, direct patient-clinician interactions and external messaging, and a third thematic category involving healthcare system-related factors and interventions. The messaging strategy identified as most useful was promoting the HPV vaccine for cancer prevention. The need for stakeholders to prioritize HPV vaccination uptake was identified as a key factor to increasing HPV vaccination rates. Multiple providers and stakeholders identified misinformation spread through social media as a barrier to HPV vaccine uptake. CONCLUSION: Emphasizing the HPV vaccine's cancer prevention benefits and prioritizing it among healthcare stakeholders were the most consistently cited strategies for promoting HPV vaccine uptake. Methods to combat the negative influence of misinformation about HPV vaccines in social media are an urgent priority.

A Web-Based Human Papillomavirus Vaccination Intervention for Young Gay, Bisexual, and Other Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial.

BACKGROUND: Gay, bisexual, and other men who have sex with men experience several disparities related to human papillomavirus (HPV) infection, including high incidence rates of anal cancer. Although the HPV vaccine is currently recommended for young adults, HPV vaccine coverage is modest among young gay, bisexual, and other men who have sex with men (YGBMSM). OBJECTIVE: We describe the design and methods for a randomized controlled trial (RCT) to rigorously evaluate Outsmart HPV, a population-targeted, individually tailored, Web-based HPV vaccination intervention for YGBMSM. The RCT is designed to determine the efficacy of the intervention, the mechanism by which the intervention has an effect (ie, mediation), and whether efficacy varies by participant characteristics (ie, moderation). METHODS: Outsmart HPV was previously developed and pilot-tested. This study is a 3-arm prospective RCT that will enroll a projected 1995 YGBMSM who are aged 18 to 25 years, live in the United States, and have not received any doses of the HPV vaccine. Participants will be recruited by means of paid advertisements on social media sites and randomized to receive (1) standard information on the Web about HPV vaccine (control group), (2) Outsmart HPV content on the Web with monthly unidirectional vaccination reminders sent via text messages, or (3) Outsmart HPV content on the Web with monthly interactive vaccination reminders sent via text messages. Participants will complete Web-based surveys at 4 time points during the study: baseline, immediately after engaging with Web-based content, 3 months after randomization, and 9 months after randomization. Primary outcomes will include both HPV vaccine initiation (ie, receipt of 1 or more doses of the HPV vaccine) and completion (receipt of all 3 doses recommended for this age range). We will examine constructs from the intervention's theoretical framework as potential mediators and demographic and health-related characteristics as potential moderators of intervention effects. RESULTS: The institutional review board at The Ohio State University has approved the study. Materials have been developed and finalized for all study groups. Recruitment for the RCT began in fall 2019. CONCLUSIONS: If shown to be efficacious, Outsmart HPV has the potential to fill an important gap by promoting HPV vaccination among a population at increased risk of HPV infection and HPV-related disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04032106; http://clinicaltrials.gov/show/NCT04032106. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/16294.

Analytics of Cerebrospinal Fluid MicroRNA Quantitative PCR Studies.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional gene expression. Recent studies have shown that human disease states correlate with measurable differences in the level of circulating miRNAs relative to healthy controls. Thus, there is great interest in developing clinical miRNA assays as diagnostic or prognostic biomarkers for diseases, and as surrogate measures for therapeutic outcomes. Our studies have focused on miRNAs in human cerebral spinal fluid (CSF) as biomarkers for central nervous system (CNS) diseases. Our objective here was to examine factors that may affect the outcome of quantitative PCR (qPCR) studies on CSF miRNAs, in order to guide planning and interpretation of future CSF miRNA TaqMan® low-density array (TLDA) studies. We obtained CSF from neurologically normal (control) donors and used TLDAs to measure miRNA expression. We examined sources of error in the TLDA outcomes due to (1) nonspecific amplification of products in total RNA, (2) variations in RNA isolations performed on different days, (3) miRNA primer probe efficiency, and (4) variations in individual TLDA cards. We also examined the utility of card-to-card TLDA corrections and use of an unchanged "reference standard" to remove batch processing effects in large-scale studies.

Improving Transitions of Care for Hospitalized Patients on Warfarin.

BACKGROUND: Transitions in care create challenges for warfarin management, including dosing errors, medication nonadherence, and/or insufficient monitoring. Adverse drug events from warfarin following transitions have been found to have serious consequences. Before the intervention, at the time of hospital discharge, individual physicians identified warfarin management plans on paper forms on the basis of their personal practice preferences. With the implementation of a computerized physician order entry in the electronic health record (EHR) in November 2010, the paper form became obsolete. A modification to the EHR created an order prompting physicians to include five key elements for warfarin management on discharge. A study was conducted to assess the impact of this intervention as a communication tool for patients and health care providers. METHODS: Discharge documentation was retrospectively reviewed for warfarin patients discharged from University of Missouri (MU) Health Care (Columbia). Frequencies of documentation in the EHR of five key elements of warfarin management were calculated (indication for anticoagulation, target International Normalized Ratio (INR) range, anticipated duration of therapy, date of next INR, and posthospital provider to manage warfarin therapy) pre- and post-EHR modification. RESULTS: All five key elements were included in the discharge documents for 268 (42%) of the charts for 633 patients in the preintevention (baseline) period, for 297 (78%) of the 382 charts in the first postintervention period (September 15, 2013-March 15, 2014) and for 574 (61%) of the 943 charts in the second postintervention period (March 16, 2014-August 5, 2015). CONCLUSIONS: Although limited to one health care system's experience, this study demonstrates the EHR's potential value in assisting with anticoagulation therapy between outpatient and inpatient settings and across multiple providers.

Microbes As Friends, Not Foes: Shifting the Focus from Pathogenesis to Symbiosis.

Until about two decades ago, the standard method of studying a microbe was to isolate it, grow it in culture, stain it, and examine it under a microscope. Today, new genomic tools are helping expand our view of the microbial world. Instead of viewing them as "germs" to be eliminated, we are beginning to perceive our microbes as an extension of ourselves - an important organ with unique functions essential to our well-being. Scientists even came up with a new term, "microbiome," to define our microbes' genes as an important counterpart to our human genome. With new information about the human microbiome comes the challenge of shifting biology students' focus from casting microbes as pathogens toward appreciating microbes as symbionts. "The Human Microbiome," a curriculum supplement produced by the Genetic Science Learning Center, emphasizes that microbes living in and on our bodies perform neutral and beneficial functions, that human microbiota form thriving ecosystems, and that disruptions to our microbial ecosystems may have consequences. In this article, we describe the curriculum materials, provide strategies for incorporating this cutting-edge topic into biology classrooms, list connections to the Next Generation Science Standards, and report on recent research testing the curriculum supplement's effectiveness for student learning.

Beyond the Central Dogma: Bringing Epigenetics into the Classroom.

Epigenetics is the study of how external factors and internal cellular signals can lead to changes in the packaging and processing of DNA sequences, thereby altering the expression of genes and traits. Exploring the epigenome introduces students to environmental influences on our genes and the complexities of gene expression. A supplemental curriculum module developed by the Genetic Science Learning Center (GSLC) at the University of Utah brings epigenetics to high school and undergraduate classrooms through a range of online and paper-based activities. We describe these activities and provide strategies for incorporating both introductory and more advanced materials that explore "cell memory," epigenetic inheritance, nutrition, and emerging connections between the epigenome and behavior. Finally, we outline recent reach on student learning gains using the GSLC's epigenetics module and provide connections to the Next Generation Science Standards.

Agonist-promoted homologous desensitization of human airway smooth muscle bitter taste receptors.

Bitter taste receptors (TAS2Rs) were shown to be expressed in human airway smooth muscle (ASM). They couple to specialized [Ca(2+)](i) release, leading to membrane hyperpolarization, the relaxation of ASM, and marked bronchodilation. TAS2Rs are G-protein-coupled receptors, known to undergo rapid agonist-promoted desensitization that can limit therapeutic efficacy. Because TAS2Rs represent a new drug target for treating obstructive lung disease, we investigated their capacity for rapid desensitization, and assessed their potential mechanisms. The pretreatment of human ASM cells with the prototypic TAS2R agonist quinine resulted in a 31% ± 5.1% desensitization of the [Ca(2+)](i) response from a subsequent exposure to quinine. No significant change in the endothelin-stimulated [Ca(2+)](i) response was attributed to the short-term use of quinine, indicating a homologous form of desensitization. The TAS2R agonist saccharin also evoked desensitization, and cross-compound desensitization with quinine was evident. Desensitization of the [Ca(2+)](i) response was attenuated by a dynamin inhibitor, suggesting that receptor internalization (a G-protein coupled receptor kinase [GRK]-mediated, ß-arrestin-mediated process) plays an integral role in the desensitization of TAS2R. Desensitization was insensitive to antagonists of the second messenger kinases protein kinase A and protein kinase C. Using intact airways, short-term, agonist-promoted TAS2R desensitization of the relaxation response was also observed. Thus these receptors, which represent a potential novel target for direct bronchodilators, undergo a modest degree of agonist-promoted desensitization that may affect clinical efficacy. Collectively, the results of these mechanistic studies, along with the multiple serines and threonines in intracellular loop 3 and the cytoplasmic tail of TAS2Rs, suggest a GRK-mediated mode of desensitization.

Paradoxical attenuation of ß2-AR function in airway smooth muscle by Gi-mediated counterregulation in transgenic mice overexpressing type 5 adenylyl cyclase.

The limiting component within the receptor-G protein-effector complex in airway smooth muscle (ASM) for ß(2)-adrenergic receptor (ß(2)-AR)-mediated relaxation is unknown. In cardiomyocytes, adenylyl cyclase (AC) is considered the "bottleneck" for ß-AR signaling, and gene therapy trials are underway to increase inotropy by increasing cardiac AC expression. We hypothesized that increasing AC in ASM would increase relaxation from ß-agonists, thereby providing a strategy for asthma therapy. Transgenic (TG) mice were generated with approximately two- to threefold overexpression of type 5 AC (AC5) in ASM. cAMP and airway relaxation in response to direct activation of AC by forskolin were increased in AC5-TG. Counter to our hypothesis, isoproterenol-mediated airway relaxation was significantly attenuated (∼50%) in AC5-TG, as was cAMP production, suggesting compensatory regulatory events limiting ß(2)-AR signaling when AC expression is increased. In contrast, acetylcholine-mediated contraction was preserved. G(αi) expression and ERK1/2 activation were markedly increased in AC5-TG (5- and 8-fold, respectively), and ß-AR expression was decreased by ∼40%. Other G proteins, G protein-coupled receptor kinases, and ß-arrestins were unaffected. ß-agonist-mediated airway relaxation of AC5-TG was normalized to that of nontransgenic mice by pertussis toxin, implicating ß(2)-AR coupling to the increased G(i) as a mechanism of depressed agonist-promoted relaxation in these mice. The decrease in ß(2)-AR may account for additional relaxation impairment, given that there is no enhancement over nontransgenic after pertussis toxin, despite AC5 overexpression. ERK1/2 inhibition had no effect on the phenotype. Thus perturbing the ratio of ß(2)-AR to AC in ASM by increasing AC fails to improve (and actually decreases) ß-agonist efficacy due to counterregulatory events.

Common ADRB2 haplotypes derived from 26 polymorphic sites direct beta2-adrenergic receptor expression and regulation phenotypes.

BACKGROUND: The beta2-adrenergic receptor (beta2AR) is expressed on numerous cell-types including airway smooth muscle cells and cardiomyocytes. Drugs (agonists or antagonists) acting at these receptors for treatment of asthma, chronic obstructive pulmonary disease, and heart failure show substantial interindividual variability in response. The ADRB2 gene is polymorphic in noncoding and coding regions, but virtually all ADRB2 association studies have utilized the two common nonsynonymous coding SNPs, often reaching discrepant conclusions. METHODOLOGY/PRINCIPAL FINDINGS: We constructed the 8 common ADRB2 haplotypes derived from 26 polymorphisms in the promoter, 5'UTR, coding, and 3'UTR of the intronless ADRB2 gene. These were cloned into an expression construct lacking a vector-based promoter, so that beta2AR expression was driven by its promoter, and steady state expression could be modified by polymorphisms throughout ADRB2 within a haplotype. "Whole-gene" transfections were performed with COS-7 cells and revealed 4 haplotypes with increased cell surface beta2AR protein expression compared to the others. Agonist-promoted downregulation of beta2AR protein expression was also haplotype-dependent, and was found to be increased for 2 haplotypes. A phylogenetic tree of the haplotypes was derived and annotated by cellular phenotypes, revealing a pattern potentially driven by expression. CONCLUSIONS/SIGNIFICANCE: Thus for obstructive lung disease, the initial bronchodilator response from intermittent administration of beta-agonist may be influenced by certain beta2AR haplotypes (expression phenotypes), while other haplotypes may influence tachyphylaxis during the response to chronic therapy (downregulation phenotypes). An ideal clinical outcome of high expression and less downregulation was found for two haplotypes. Haplotypes may also affect heart failure antagonist therapy, where beta2AR increase inotropy and are anti-apoptotic. The haplotype-specific expression and regulation phenotypes found in this transfection-based system suggest that the density of genetic information in the form of these haplotypes, or haplotype-clusters with similar phenotypes can potentially provide greater discrimination of phenotype in human disease and pharmacogenomic association studies.

Association of attention-deficit/hyperactivity disorder with a candidate region for reading disabilities on chromosome 6p.

BACKGROUND: Reading disabilities (RD) and attention-deficit hyperactivity/disorder (ADHD) are two common childhood disorders that co-occur by chance more often than expected. Twin studies and overlapping genetic linkage findings indicate that shared genetic factors partially contribute to this comorbidity. Linkage of ADHD to 6p, an identified RD candidate locus, has previously been reported, suggesting the possibility of a pleiotropic gene at this locus. RD has been previously associated with five genes in the region, particularly DCDC2 and KIAA0319. METHODS: To test whether these genes also contribute to ADHD, we investigated markers previously associated with RD for association with ADHD and ADHD symptoms in a sample of families with ADHD (n = 264). Markers were located in two subregions, VMP/DCDC2 and KIAA0319/TTRAP. RESULTS: Across all analyses conducted, strong evidence for association was observed in the VMP/DCDC2 region. Association was equally strong with symptoms of both inattention and hyperactivity/impulsivity, suggesting that this locus contributes to both symptom dimensions. Markers were also tested for association with measures of reading skills (word identification, decoding); however, there was virtually no overlap in the markers associated with ADHD and those associated with reading skills in this sample. CONCLUSIONS: Overall this study supports a previous linkage study of ADHD indicating a risk gene for ADHD on 6p and points to VMP or DCDC2 as the most likely candidates.

Association study for genes at chromosome 5p13-q11 in attention deficit hyperactivity disorder.

Linkage of attention deficit hyperactivity disorder (ADHD) to the short arm-centromeric region of chromosome 5 has been reported in multiple studies. The overlapping region (5p13-q11) contains a number of strong candidate genes for ADHD, based on their role in brain function or neurodevelopment. The aim of this study was to investigate some of the top candidates among these genes in relation to ADHD in a sample of 245 nuclear families from the Toronto area. We investigated the genes for the glial cell-derived neurotropic factor (GDNF), the fibroblast growth factor 10 (FGF10), islet-1 (ISL1), the hyperpolarized potassium channel (HCN1) and the integrin alpha 1 (ITGA1). In addition to these genes, we assessed the 3'region of the SLC1A3 gene, a glutamate transporter implicated in ADHD by a previous association study. A total of 36 polymorphisms were selected across the six genes. We performed family-based association and haplotype analyses. ADHD is a dimensional disorder, with symptoms of inattention and hyperactivity-impulsivity therefore, we also conducted quantitative analysis in relation to symptom scores for both dimensions. Single marker and haplotype analyses yielded little evidence of association for any of the genes tested in this study. Moreover, we were unable to replicate the positive association findings reported for SLC1A3. Our results suggest that these six genes are unlikely to be susceptibility genes in the chromosome 5p13-q11 region and other genes should now be considered for priority study.

No evidence for genetic association between DARPP-32 (PP1R1B) polymorphisms and attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests that a dopamine system dysfunction plays a role in the disorder pathophysiology. Several genes involved in dopamine neurotransmission have shown replicated genetic association with ADHD. These include the dopamine receptors D4 (DRD4), D5 (DRD5), and the dopamine transporter (DAT1) genes. Recently, evidence has also accumulated in favor of the dopamine receptor D1 gene (DRD1). The dopamine- and cAMP-regulated phosphoprotein of relative molecular mass of 32 kDa (DARPP-32) is a key component of dopamine signaling, acting as a converging point for several neurotransmitter systems influencing dopaminergic neurons and regulating a wide variety of downstream effectors. Here, we tested the DARPP-32 gene, PPP1R1B, for association with ADHD using four polymorphic markers selected across the gene in a sample of 255 ADHD families. We did not detect evidence of association of individual marker alleles and haplotype analysis did not reveal significant association in this sample of families. Moreover, we found no relationship between the same alleles or haplotypes and symptom scores of inattention or hyperactivity/impulsivity in these families using a quantitative approach. In conclusion, albeit a key regulatory role in dopamine signaling, our data do not support a major contribution of the DARPP-32 gene in ADHD.

Investigation of the G protein subunit Galphaolf gene (GNAL) in attention deficit/hyperactivity disorder.

The dopamine system plays an important role in the regulation of attention and motor behavior, subsequently, several dopamine-related genes have been associated with Attention Deficit/Hyperactivity Disorder (ADHD). Among them are the dopamine receptors D1 and D5 that mediate adenylyl cyclase activation through coupling with G(s)-like proteins. We thus hypothesized that the G(s)-like subunit Galpha(olf), expressed in D1-rich areas of the brain, contributes to the genetic susceptibility of ADHD. To evaluate the involvement of the Galpha(olf) gene, GNAL, in ADHD, we examined the inheritance pattern of 12 GNAL polymorphisms in 258 nuclear families ascertained through a proband with ADHD (311 affected children) using the transmission/disequilibrium test (TDT). Categorical analysis of individual marker alleles demonstrated biased transmission of one polymorphism in GNAL intron 3 (rs2161961; P=0.011). We also observed significant relationships between rs2161961 and dimensional symptoms of inattention and hyperactivity/impulsivity (P=0.003 and P=0.008). In addition, because of recent evidence of imprinting at the GNAL locus, secondary analyses were split into maternal and paternal transmissions to assess a contribution of parental effects. We found evidence of strong maternal effect, with preferential transmission of maternal alleles for rs2161961A (P=0.005) and rs8098539A (P=0.035). These preliminary findings suggest a possible contribution of GNAL in the susceptibility to ADHD, with possible involvement of parent-of-origin effects.

Association study of the brain-derived neurotropic factor (BDNF) gene in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental childhood psychiatric disorder. Brain-derived neurotropic factor (BDNF) has been suggested to play a role in the pathogenesis of ADHD and two family-based association studies demonstrated an association of BDNF polymorphisms with ADHD. The aim of the current study was to investigate the BDNF gene for association with ADHD in a large sample of families from Toronto. The transmission of three polymorphisms of the BDNF gene (rs6265, rs11030104, and rs2049046) was examined in 266 nuclear families ascertained through a proband with ADHD (315 affected children) using the transmission/disequilibrium test (TDT). In addition, we conducted quantitative analysis to assess the relationship between these marker alleles and the symptom dimensions of ADHD (inattention and hyperactivity/impulsivity) and cognitive measures of working memory. None of the individual marker alleles showed significant evidence of association with ADHD, dimensional symptom scores, or working memory ability in our sample of ADHD families. There was no significant evidence for biased transmission of individual haplotypes with frequency >10% (global chi2 for these three haplotypes: chi2 = 6.349, df = 3, P = 0.096). One uncommon haplotype (A-G-G; frequency 2.2%) showed a significant association with ADHD in the categorical (chi2 = 5.293, df = 1, P = 0.021) and quantitative analyses (parents' rated inattention: Z = -2.504, P = 0.012; and hyperactivity/impulsivity: Z = -2.651, P = 0.008). These results should be interpreted cautiously, however, because of the low haplotype frequency. In light of the evidence for an involvement of BDNF in ADHD, further analysis of the BDNF gene in ADHD is warranted.

The gene for synapsin III and attention-deficit hyperactivity disorder.

OBJECTIVE: Recent studies have implicated the involvement of proteins regulating neurotransmitter release in the etiology of attention deficit hyperactivity disorder. On the basis of the role of synapsin III in the modulation of neurotransmitter release, we tested this gene as a candidate contributing to the genetic susceptibility of attention deficit hyperactivity disorder. METHOD: In this study, we genotyped five markers across the gene on 177 small, nuclear families consisting of an attention deficit hyperactivity disorder proband, their parents, and 43 affected siblings. We examined the transmission of the alleles at each one of these sites and the haplotypes of the polymorphisms using the transmission disequilibrium test. RESULT: Our observations did not yield any evidence of biased transmission of the alleles at any polymorphism or haplotype. On the basis of the evidence for synapsins in learning and memory from animal models, we also investigated the relationship of this gene to verbal short-term and working memory as measured by digit span forward and backwards. No evidence was found for an association of this gene to these traits. CONCLUSION: Our findings with this particular sample do not support the synapsin III locus as a major susceptibility locus contributing to attention deficit hyperactivity disorder.