Characteristics and early clinical outcomes of patients undergoing totally subcutaneous vs. transvenous single chamber implantable cardioverter defibrillator placement.

Aims: In 2012, the first totally Subcutaneous Implantable Cardioverter-Defibrillator (S-ICD) was approved by the Food and Drug Administration (FDA) in the United States. A possible benefit of this device is that it does not involve placing leads 'in' or 'on' the heart, potentially reducing complications. Methods amd results: Ninety-one S-ICD and 182 single chamber TV-ICD implants were performed between 10/22/2012 and 9/22/2015. During this period of time, 91 patients with S-ICD were matched to TV-ICD patients using single centre NCDR ICD Registry Data based on dialysis status, gender, and age. Intra- and post-operative complications and deaths were examined within the first 180 days following implantation. Patients with S-ICDs had higher creatinine (2.3 ± 2.5 vs. 1.1 ± 0.7, P < 0.001) and were more likely to be on chronic dialysis (20.9% vs. 5.5%, P < 0.001) than TV-ICD patients. Patients in the S-ICD group were more likely to have had prior device infections (14.3% vs. 3.3%, P = 0.021) as well as prior TIA/CVA (14.3% vs. 4.4%, P = 0.049) compared to patients in the TV-ICD group. Seven patients experienced 7 complications or death in TV-ICD group and 5 patients experienced 7 complications or death in SQ-ICD group, P = 0.774. Conclusion: In this retrospective matched single centre cohort study, there was no significant difference in implantation complications or death in patients receiving single chamber TV-ICDs compared to S-ICDs within 6 months following implantation. This occurred despite more severe preexisting illness in the S-ICD group. Further investigation is needed to determine outcomes after longer-term follow-up.

Sleep restriction worsens mood and emotion regulation in adolescents.

BACKGROUND: The relationship between inadequate sleep and mood has been well-established in adults and is supported primarily by correlational data in younger populations. Given that adolescents often experience shortened sleep on school nights, we sought to better understand the effect of experimentally induced chronic sleep restriction on adolescents' mood and mood regulation. METHODS: Fifty healthy adolescents, ages 14-17, completed a 3-week sleep manipulation protocol involving a baseline week, followed by a sleep restriction (SR) condition (6.5 hr in bed per night for five nights) and healthy sleep duration (HS) condition (10 hr in bed per night for five nights). The study used a randomized, counterbalanced, crossover experimental design. Participants' sleep was monitored at home via self-report and actigraphy. At the end of each condition, participants and their parents completed questionnaires of mood and mood regulation. To assess for expectancy effects, we also analyzed parent and teen ratings of hyperactivity/impulsivity, which prior research suggests is not sensitive to SR in adolescents. Wilcoxon Signed Rank tests compared questionnaire outcomes across the two conditions. RESULTS: Participants averaged 2.5 more hours of sleep per night during HS relative to SR. Compared with HS, adolescents rated themselves as significantly more tense/anxious, angry/hostile, confused, and fatigued, and as less vigorous (p = .001-.01) during SR. Parents and adolescents also reported greater oppositionality/irritability and poorer emotional regulation during SR compared with HS (p < .05). There were no cross-condition differences in depression or hyperactivity/impulsivity (p > .05). CONCLUSIONS: Findings complement prior correlational study results to show that after only a few days of shortened sleep, at a level of severity that is experienced regularly by millions of adolescents on school nights, adolescents have worsened mood and decreased ability to regulate negative emotions.

Household expansion linked to agricultural intensification during emergence of Hawaiian archaic states.

The Leeward Kohala Field System (LKFS) covering ∼ 60 km(2) on Hawai'i Island is one of the world's best-studied archaeological examples of preindustrial agricultural intensification. Archaeological correlates for households over a 400-y period of intensification of the LKFS (A.D. 1400-1800) indicate that household age, number, and distribution closely match the expansion of agricultural features at both macro- and microscales. We excavated and dated residential complexes within portions of five traditional Hawaiian land units (ahupua'a), two in the central core of the field system and three in the southern margins. Forty-eight radiocarbon dates from 43 residential features indicate an overall pattern of exponential increase in the numbers of households over time. Spatial distribution of these dates suggests that the core of the LKFS may have reached a population saturation point earlier than in the southern margins. Bayesian statistical analysis of radiocarbon dates from residential features in the core region, combined with spatial analysis of agricultural and residential construction sequences, demonstrates that the progressive subdivision of territories into smaller socioeconomic units was matched by addition of new residences, probably through a process of household fissioning. These results provide insights into the economic processes underlying the sociopolitical transformation from chiefdom to archaic state in precontact Hawai'i.

Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter.

Serotonin [i.e., 5-hydroxytryptamine (5-HT)]-targeted antidepressants are in wide use for the treatment of mood disorders, although many patients do not show a response or experience unpleasant side effects. Psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (i.e., "ecstasy"), also impact 5-HT signaling. To help dissect the contribution of 5-HT signaling to the actions of these and other agents, we developed transgenic mice in which high-affinity recognition of multiple antidepressants and cocaine is eliminated. Our animals possess a modified copy of the 5-HT transporter (i.e., SERT, slc6a4) that bears a single amino acid substitution, I172M, proximal to the 5-HT binding site. Although the M172 substitution does not impact the recognition of 5-HT, this mutation disrupts high-affinity binding of many competitive antagonists in transfected cells. Here, we demonstrate that, in M172 knock-in mice, basal SERT protein levels, 5-HT transport rates, and 5-HT levels are normal. However, SERT M172 mice display a substantial loss of sensitivity to the selective 5-HT reuptake inhibitors fluoxetine and citalopram, as well as to cocaine. Through a series of biochemical, electrophysiological, and behavioral assays, we demonstrate the unique properties of this model and establish directly that SERT is the sole protein responsible for selective 5-HT reuptake inhibitor-mediated alterations in 5-HT clearance, in 5-HT1A autoreceptor modulation of raphe neuron firing, and in behaviors used to predict the utility of antidepressants.

Electronic health record design and implementation for pharmacogenomics: a local perspective.

PURPOSE: The design of electronic health records to translate genomic medicine into clinical care is crucial to successful introduction of new genomic services, yet there are few published guides to implementation. METHODS: The design, implemented features, and evolution of a locally developed electronic health record that supports a large pharmacogenomics program at a tertiary-care academic medical center was tracked over a 4-year development period. RESULTS: Developers and program staff created electronic health record mechanisms for ordering a pharmacogenomics panel in advance of clinical need (preemptive genotyping) and in response to a specific drug indication. Genetic data from panel-based genotyping were sequestered from the electronic health record until drug-gene interactions met evidentiary standards and deemed clinically actionable. A service to translate genotype to predicted drug-response phenotype populated a summary of drug-gene interactions, triggered inpatient and outpatient clinical decision support, updated laboratory records, and created gene results within online personal health records. CONCLUSION: The design of a locally developed electronic health record supporting pharmacogenomics has generalizable utility. The challenge of representing genomic data in a comprehensible and clinically actionable format is discussed along with reflection on the scalability of the model to larger sets of genomic data.

Stakeholder engagement: a key component of integrating genomic information into electronic health records.

Integrating genomic information into clinical care and the electronic health record can facilitate personalized medicine through genetically guided clinical decision support. Stakeholder involvement is critical to the success of these implementation efforts. Prior work on implementation of clinical information systems provides broad guidance to inform effective engagement strategies. We add to this evidence-based recommendations that are specific to issues at the intersection of genomics and the electronic health record. We describe stakeholder engagement strategies employed by the Electronic Medical Records and Genomics Network, a national consortium of US research institutions funded by the National Human Genome Research Institute to develop, disseminate, and apply approaches that combine genomic and electronic health record data. Through select examples drawn from sites of the Electronic Medical Records and Genomics Network, we illustrate a continuum of engagement strategies to inform genomic integration into commercial and homegrown electronic health records across a range of health-care settings. We frame engagement as activities to consult, involve, and partner with key stakeholder groups throughout specific phases of health information technology implementation. Our aim is to provide insights into engagement strategies to guide genomic integration based on our unique network experiences and lessons learned within the broader context of implementation research in biomedical informatics. On the basis of our collective experience, we describe key stakeholder practices, challenges, and considerations for successful genomic integration to support personalized medicine.

Fire activity and deforestation in Remote Oceanian islands caused by anthropogenic and climate interactions.

Remote islands in the Pacific Ocean (Oceania) experienced dramatic environmental transformations after initial human settlement in the past 3,000 yr. Here, human causality of this environmental degradation has been unquestioned and viewed as evidence of the inherent destructive tendencies of human societies in both archaeological and popular discourse. We use charcoal and stable carbon isotopes from deep soil cores to reconstruct the dynamics of fire activity and deforestation across the Sigatoka River valley on the leeward (dry) side of Viti Levu, Fiji. Fires and pyrogenic patches of grassland predated human settlement by millennia, but the magnitude of fire activity and landscape transformation accelerated with the establishment and expansion of swidden agriculture. Regional comparisons with previous studies in Fiji and elsewhere in Remote Oceania settled between 3,200 and 2,900 yr BP reveal a similar pattern of pre- and post-settlement fire activity and landscape change. Pre-settlement fires generally corresponded to droughts, probably driven by El Niño, often correlating with drought-driven wildfires elsewhere in the region. Post-settlement, charcoal and C4 grasses increased dramatically, but nearly all major peaks in charcoal and grasses corresponded to increased El Niño activity. This indicates that fire activity and deforestation were a product of the interaction between swidden agriculture and climate rather than land use alone.

A conserved asparagine residue in transmembrane segment 1 (TM1) of serotonin transporter dictates chloride-coupled neurotransmitter transport.

Na(+)- and Cl(-)-dependent uptake of neurotransmitters via transporters of the SLC6 family, including the human serotonin transporter (SLC6A4), is critical for efficient synaptic transmission. Although residues in the human serotonin transporter involved in direct Cl(-) coordination of human serotonin transport have been identified, the role of Cl(-) in the transport mechanism remains unclear. Through a combination of mutagenesis, chemical modification, substrate and charge flux measurements, and molecular modeling studies, we reveal an unexpected role for the highly conserved transmembrane segment 1 residue Asn-101 in coupling Cl(-) binding to concentrative neurotransmitter uptake.

Technical note: The use of geographical information systems software for the spatial analysis of bone microstructure.

Geographic information systems (GIS) software is typically used for analyzing geographically distributed data, allowing users to annotate points or areas on a map and attach data for spatial analyses. While traditional GIS-based research involves geo-referenced data (points tied to geographic locations), the use of this technology has other constructive applications for physical anthropologists. The use of GIS software for the study of bone histology offers a novel opportunity to analyze the distribution of bone nano- and microstructures, relative to macrostructure and in comparison to other variables of interest, such as biomechanical loading history. This approach allows for the examination of characteristics of single histological features while considering their role at the macroscopic level. Such research has immediate promise in examining the load history of bone by surveying the functional relationship between collagen fiber orientation (CFO) and strain mode. The diversity of GIS applications that may be utilized in bone histology research is just beginning to be explored. The goal of this study is to introduce a reliable methodology for such investigation and our objective is to quantify the heterogeneity of bone microstructure over an entire cross-section of bone using ArcGIS v 9.3 (ESRI). This was accomplished by identifying the distribution of remodeling units in a human metatarsal relative to bending axes. One biomechanical hypothesis suggests that CFO, manifested by patterns of birefringence, is indicative of mode of strain during formation. This study demonstrates that GIS can be used to investigate, describe, and compare such patterns through histological mapping.

Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylene dioxymethamphetamine.

The plasma membrane serotonin (5-HT) transporter (SERT, SLC6A4) clears 5-HT after release at nerve termini and is targeted by both antidepressant medications and psychostimulants (e.g. MDMA, cocaine). Homology modeling of human SERT (hSERT), based on high resolution structures of the microbial SLC6 family member LeuT(Aa), along with biochemical studies of wild type and mutant transporters, predicts transmembrane (TM) domains 1, 3, 6, and 8 comprise the 5-HT-binding pocket. We utilized the substituted cysteine accessibility method along with surface and site-specific biotinylation to probe TM6 for aqueous accessibility and differential interactions with 5-HT and psychostimulants. Our results are consistent with TM6 being composed of an aqueous-accessible, alpha-helical extracellular domain (TM6a) that is separated by a central, unwound section from a cytoplasmically localized domain (TM6b) with limited aqueous accessibility. The substitution G338C appears to lock hSERT in an outward-facing conformation that, although accessible to aminoethylmethanethiosulfonate-biotin, 5-HT, and citalopram, is incapable of inward 5-HT transport. Transport of 5-HT by G338C can be partially restored by the TM1 mutation Y95F. With regard to methanethiosulfonate (MTS) inactivation of uptake, TM6a Cys mutants demonstrate Na(+)-dependent [2-(trimethylammonium)ethyl]-MTS sensitivity. Studies with the centrally located substitution S336C reveal features of a common binding pocket for 5-HT and 3,4-methylenedioxymethamphetamine (MDMA). Interestingly, the substitution I333C reveals an MDMA-induced conformation not observed with 5-HT. In the context of prior studies on TM1, our findings document shared and unique features of TM6 contributing to hSERT aqueous accessibility, ligand recognition, and conformational dynamics.

Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies.

To identify potential determinants of substrate selectivity in serotonin (5-HT) transporters (SERT), models of human and Drosophila serotonin transporters (hSERT, dSERT) were built based on the leucine transporter (LeuT(Aa)) structure reported by Yamashita et al. (Nature 2005;437:215-223), PBDID 2A65. Although the overall amino acid identity between SERTs and the LeuT(Aa) is only 17%, it increases to above 50% in the first shell of the putative 5-HT binding site, allowing de novo computational docking of tryptamine derivatives in atomic detail. Comparison of hSERT and dSERT complexed with substrates pinpoints likely structural determinants for substrate binding. Forgoing the use of experimental transport and binding data of tryptamine derivatives for construction of these models enables us to critically assess and validate their predictive power: A single 5-HT binding mode was identified that retains the amine placement observed in the LeuT(Aa) structure, matches site-directed mutagenesis and substituted cysteine accessibility method (SCAM) data, complies with support vector machine derived relations activity relations, and predicts computational binding energies for 5-HT analogs with a significant correlation coefficient (R = 0.72). This binding mode places 5-HT deep in the binding pocket of the SERT with the 5-position near residue hSERT A169/dSERT D164 in transmembrane helix 3, the indole nitrogen next to residue Y176/Y171, and the ethylamine tail under residues F335/F327 and S336/S328 within 4 A of residue D98. Our studies identify a number of potential contacts whose contribution to substrate binding and transport was previously unsuspected.

Impact of Multi-Night Experimentally Induced Short Sleep on Adolescent Performance in a Simulated Classroom.

Study Objectives: Investigate whether a realistic "dose" of shortened sleep, relative to a well-rested state, causes a decline in adolescents' learning and an increase in inattentive and sleepy behaviors in a simulated classroom setting. Methods: Eighty-seven healthy 14.0- to 16.9-year olds underwent a 3-week sleep manipulation protocol, including two 5-night sleep manipulation conditions presented in a randomly counterbalanced within-subjects cross-over design. Wake time was held constant. Bedtimes were set to induce Short Sleep (SS; 6.5 hours in bed) versus Healthy Sleep (HS; 10 hours in bed). During the morning at the end of each condition, participants underwent a simulated classroom procedure in which they viewed lecture-based educational videotapes and completed relevant quizzes. Their behaviors in the simulated classroom were later coded by condition-blind raters for evidence of inattention and sleepiness. Results: Adolescents had a longer average sleep period during HS (9.1 hours) than SS (6.5 hours). Compared to scores during HS, adolescents scored significantly lower on the quiz, showed more behaviors suggestive of inattention and sleepiness in the simulated classroom, and were reported by adolescents themselves and by their parents to be more inattentive and sleepy during SS. However, the impact of the manipulation on quiz scores was not mediated by changes in attention or sleepiness. Conclusions: Although effect sizes were modest, these findings suggest that previously-reported correlations between sleep duration and academic performance reflect true cause-effect relationships. Findings add to the growing evidence that the chronically shortened sleep experienced by many adolescents on school nights adversely impacts their functioning and health.

A prognostic model based on readily available clinical data enriched a pre-emptive pharmacogenetic testing program.

OBJECTIVES: We describe the development, implementation, and evaluation of a model to pre-emptively select patients for genotyping based on medication exposure risk. STUDY DESIGN AND SETTING: Using deidentified electronic health records, we derived a prognostic model for the prescription of statins, warfarin, or clopidogrel. The model was implemented into a clinical decision support (CDS) tool to recommend pre-emptive genotyping for patients exceeding a prescription risk threshold. We evaluated the rule on an independent validation cohort and on an implementation cohort, representing the population in which the CDS tool was deployed. RESULTS: The model exhibited moderate discrimination with area under the receiver operator characteristic curves ranging from 0.68 to 0.75 at 1 and 2 years after index dates. Risk estimates tended to underestimate true risk. The cumulative incidences of medication prescriptions at 1 and 2 years were 0.35 and 0.48, respectively, among 1,673 patients flagged by the model. The cumulative incidences in the same number of randomly sampled subjects were 0.12 and 0.19, and in patients over 50 years with the highest body mass indices, they were 0.22 and 0.34. CONCLUSION: We demonstrate that prognostic algorithms can guide pre-emptive pharmacogenetic testing toward those likely to benefit from it.

The IGNITE network: a model for genomic medicine implementation and research.

BACKGROUND: Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility. METHODS: To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org ) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches. RESULTS: This paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years. CONCLUSIONS: The IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.

Clinician Perspectives on Using Pharmacogenomics in Clinical Practice.

AIM: To describe the knowledge and attitudes of clinicians participating in a large pharmacogenomics implementation program. MATERIALS & METHODS: Semi-structured interviews with 15 physicians and nurse practitioners were conducted. RESULTS: Three categories of themes were identified: preparation and knowledge, pharmacogenomics usage in practice, and future management of genomic variants. Providers expressed an inability to keep up with the rapid pace of evidence generation and indicated strong support for clinical decision support to assist with genotype-tailored therapies. Concerns raised by clinicians included effectively communicating results, long-term responsibility for actionable results and hand-offs with providers outside the implementation program. CONCLUSIONS: Clinicians identified their own knowledge deficits, workflow integration, and longitudinal responsibility as challenges to successful usage of pharmacogenomics in clinical practice.

Impact of experimentally manipulated sleep on adolescent simulated driving.

OBJECTIVE/BACKGROUND: Sleep restriction (SR) impairs adolescents' attention, which could contribute to high rates of driving crashes. Here, we examine the impact of experimental SR on adolescent drivers, considering whether that impact is moderated by the nature of the drive (urban/suburban vs. rural) or how vulnerable each adolescent is to attentional decline after SR. PARTICIPANTS/METHODS: A total of 17 healthy 16-18-year-old licensed drivers completed two five-night sleep conditions: SR (6.5 h in bed) versus extended sleep (ES; 10 h in bed) in counterbalanced order. After each, participants completed rural and urban/suburban courses in a driving simulator, and parents rated participants' attention in day-to-day settings. Vulnerability to SR was computed as cross-condition change in parent ratings. Dependent variables included standard deviation (SD) of lateral lane position (SDLP), mean speed, SD of speed, and crashes. Multivariate models examined the main and interaction effects of sleep condition, driving environment, and vulnerability to SR, covarying for years licensed. RESULTS: Although the effects for the other outcomes were nonsignificant, there were three-way interactions (sleep × drive × vulnerability) for mean speed and SDLP (p <0.02). During the rural drive, adolescents had less consistent lateral vehicle control in SR than ES, despite slower driving among those reported to be vulnerable to SR. During the urban/suburban drive, SR worsened SDLP only among adolescents reported to be vulnerable to SR. CONCLUSIONS: These preliminary findings suggest that even a moderate degree of SR may be a modifiable contributor to adolescent driving problems for some. This impact is widely present during monotonous rural drives and in a subgroup during interesting urban/suburban drives.

Sweet/dessert foods are more appealing to adolescents after sleep restriction.

STUDY OBJECTIVE: Examine the effect of experimental sleep restriction (SR) on adolescents' subjective hunger and perceived appeal of sweet/dessert foods versus other foods. A secondary goal was to replicate previous findings on the effects of SR on dietary intake. DESIGN: Randomized cross-over sleep restriction-extension paradigm. SETTING: Sleep was obtained and monitored at home. Outcome measures were gathered during office visits. PARTICIPANTS: 31 typically-developing adolescents aged 14-17 years. INTERVENTIONS: The three-week protocol consisted of a baseline week, followed randomly by five consecutive nights of SR (6.5 hours in bed) versus healthy sleep duration (HS; 10 hours in bed), a 2-night wash-out period, and a 5-night cross-over. MEASUREMENTS: Sleep was monitored via actigraphy. The morning after each experimental condition, teens rated their hunger, underwent a 24-hour diet recall interview, and rated the appeal of a series of pictures of sweet/dessert foods (e.g., ice cream, candy) and non-sweets (meat, eggs, fruits, vegetables). RESULTS: Teens rated pictures of sweet/dessert foods to be more appealing after SR than after HS (Cohen's d = .41, t = 2.07, p = .045). The sleep manipulation did not affect self-reported hunger or the appeal of non-sweet foods (p >.10). Consistent with our prior work, intake of overall calories was 11% higher and consumption of sweet/dessert servings was 52% greater during SR than HS. CONCLUSIONS: Adolescent SR appears to increase the subjective appeal of sweet/dessert foods, indicating a potential mechanism by which SR might contribute to weight gain and the risk for obesity and chronic illness.

Biobanks and electronic medical records: enabling cost-effective research.

The use of electronic medical record data linked to biological specimens in health care settings is expected to enable cost-effective and rapid genomic analyses. Here, we present a model that highlights potential advantages for genomic discovery and describe the operational infrastructure that facilitated multiple simultaneous discovery efforts.

Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7.

Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.

Phenome-wide association studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index.

Phenome-wide association studies (PheWAS) have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR)-based PheWAS to explore pleiotropy of genetic variants in the fat mass and obesity associated gene (FTO), some of which have been previously associated with obesity and type 2 diabetes (T2D). We used a population of 10,487 individuals of European ancestry with genome-wide genotyping from the Electronic Medical Records and Genomics (eMERGE) Network and another population of 13,711 individuals of European ancestry from the BioVU DNA biobank at Vanderbilt genotyped using Illumina HumanExome BeadChip. A meta-analysis of the two study populations replicated the well-described associations between FTO variants and obesity (odds ratio [OR] = 1.25, 95% Confidence Interval = 1.11-1.24, p = 2.10 × 10(-9)) and FTO variants and T2D (OR = 1.14, 95% CI = 1.08-1.21, p = 2.34 × 10(-6)). The meta-analysis also demonstrated that FTO variant rs8050136 was significantly associated with sleep apnea (OR = 1.14, 95% CI = 1.07-1.22, p = 3.33 × 10(-5)); however, the association was attenuated after adjustment for body mass index (BMI). Novel phenotype associations with obesity-associated FTO variants included fibrocystic breast disease (rs9941349, OR = 0.81, 95% CI = 0.74-0.91, p = 5.41 × 10(-5)) and trends toward associations with non-alcoholic liver disease and gram-positive bacterial infections. FTO variants not associated with obesity demonstrated other potential disease associations including non-inflammatory disorders of the cervix and chronic periodontitis. These results suggest that genetic variants in FTO may have pleiotropic associations, some of which are not mediated by obesity.