WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Evaluation of the effect of local administration of PRP vs vitamin D3 on the rate of orthodontic tooth movement and the associated external apical root resorption.

Background: Increased orthodontic treatment duration is associated with iatrogenic risks such as root resorption, white spot lesions etc. Recent research using pharmacological agents to accelerate tooth movement has mostly been conducted on animals and there is no reported research conducted on humans comparing the effects of Vitamin D3 and Platelet Rich Plasma (PRP) in the same subjects using a split mouth technique. Objectives: To determine and compare effects of local injection of PRP and Vitamin D3 on the rate of tooth movement. Also, to assess association of external apical root resorption with the use of PRP, Vitamin D3 and compare it to a control group. Materials & methods: 11 subjects who diagnosed with Class I bi-maxillary malocclusion and who gave informed consent were recruited in the study. The patients were randomly divided using split mouth design and each quadrant served as either experimental or control group one. At the beginning of retraction phase, Vitamin D3 and PRP were injected to the randomly assigned quadrants while the contralateral side served as a control. The amount of space closure in 4 months was measured from distal surface of canine to mesial surface of 2nd premolar. Root resorption was assessed using CBCT taken at the beginning and at the closure of retraction phase. Results: Mean rate of tooth movement was higher in PRP and Vitamin D3 groups compared to their controls. In the PRP group, the increased rate of tooth movement was observed throughout the study interval, but in the Vitamin D3 group it was only seen in first two months. Also, the PRP group demonstrated a higher rate of tooth movement compared to Vitamin D3 group. Root resorption was lesser in both experimental groups. Among the teeth assessed, lateral incisor showed maximum root resorption and canine the least. Conclusions: PRP is a more efficient pharmacological agent compared to Vitamin D3 for accelerating tooth movement.

Balance Assessment of Children with Sensorineural Hearing Loss.

This study aimed to assess the balance function in children with sensorineural hearing loss (SNHL) using different tests to assess vestibulospinal pathway and tests to assess vestibular system and to compare the result obtained with those of children with normal hearing sensitivity. Detailed balance assessment was done for 15 children with severe to profound SNHL and 15 children with normal hearing sensitivity in the age range of 6-10 years. The audiological evaluation included pure-tone audiometry, speech audiometry, immittance evaluation, otoacoustic emission, vestibular evoked myogenic potential (cervical VEMP and ocular VEMP), and tests to assess vestibulospinal pathway and cerebellar function, such as Romberg test, Fukuda stepping test, Tandem gait test, and Finger-to-nose test. cVEMP and oVEMP were absent in 8 ears (27%) of a total of 30 ears with SNHL. Statistical analysis shows no significant difference between latency and amplitude of cVEMP peaks and latency of oVEMP peaks across groups. Significant reduction of oVEMP peaks amplitude was seen in children with SNHL compared to children with normal hearing. Fukuda stepping test showed an abnormal response in 2 children with SNHL (13%) and one child could not perform tandem gait test (7%). Children with SNHL showed an evident abnormality on the balance assessment test results. The abnormal function of the vestibular system and the vestibulospinal pathway can compromise the child's motor development and thus needs investigation early in life.

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10-6), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.

Characterization of genetic and phenotypic heterogeneity of obstructive sleep apnea using electronic health records.

BACKGROUND: Obstructive sleep apnea (OSA) is defined by frequent episodes of reduced or complete cessation of airflow during sleep and is linked to negative health outcomes. Understanding the genetic factors influencing expression of OSA may lead to new treatment strategies. Electronic health records (EHRs) can be leveraged to both validate previously reported OSA-associated genomic variation and detect novel relationships between these variants and comorbidities. METHODS: We identified candidate single nucleotide polymorphisms (SNPs) via systematic literature review of existing research. Using datasets available at Geisinger (n = 39,407) and Vanderbilt University Medical Center (n = 24,084), we evaluated associations between 40 previously implicated SNPs and OSA diagnosis, defined using clinical codes. We also evaluated associations between these SNPs and OSA severity measures obtained from sleep reports at Geisinger (n = 6571). Finally, we used a phenome-wide association study approach to help reveal pleiotropic genetic effects between OSA candidate SNPs and other clinical codes and laboratory values available in the EHR. RESULTS: Most previously reported OSA candidate SNPs showed minimal to no evidence for associations with OSA diagnosis or severity in the EHR-derived datasets. Three SNPs in LEPR, MMP-9, and GABBR1 validated for an association with OSA diagnosis in European Americans; the SNP in GABBR1 was associated following meta-analysis of results from both clinical populations. The GABBR1 and LEPR SNPs, and one additional SNP, were associated with OSA severity measures in European Americans from Geisinger. Three additional candidate OSA SNPs were not associated with OSA-related traits but instead with hyperlipidemia and autoimmune diseases of the thyroid. CONCLUSIONS: To our knowledge, this is one of the largest candidate gene studies and one of the first phenome-wide association studies of OSA genomic variation. Results validate genetic associates with OSA in the LEPR, MMP-9 and GABBR1 genes, but suggest that the majority of previously identified genetic associations with OSA may be false positives. Phenome-wide analyses provide evidence of mediated pleiotropy. Future well-powered genome-wide association analyses of OSA risk and severity across populations with diverse ancestral backgrounds are needed. The comprehensive nature of the analyses represents a platform for informing future work focused on understanding how genetic data can be useful to informing treatment of OSA and related comorbidities.

A genome-wide association study of polycystic ovary syndrome identified from electronic health records.

BACKGROUND: Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age. A number of criteria have been developed for clinical diagnosis of polycystic ovary syndrome, with the Rotterdam criteria being the most inclusive. Evidence suggests that polycystic ovary syndrome is significantly heritable, and previous studies have identified genetic variants associated with polycystic ovary syndrome diagnosed using different criteria. The widely adopted electronic health record system provides an opportunity to identify patients with polycystic ovary syndrome using the Rotterdam criteria for genetic studies. OBJECTIVE: To identify novel associated genetic variants under the same phenotype definition, we extracted polycystic ovary syndrome cases and unaffected controls based on the Rotterdam criteria from the electronic health records and performed a discovery-validation genome-wide association study. STUDY DESIGN: We developed a polycystic ovary syndrome phenotyping algorithm on the basis of the Rotterdam criteria and applied it to 3 electronic health record-linked biobanks to identify cases and controls for genetic study. In the discovery phase, we performed an individual genome-wide association study using the Geisinger MyCode and the Electronic Medical Records and Genomics cohorts, which were then meta-analyzed. We attempted validation of the significant association loci (P<1×10-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed-effect model was adopted for meta-analysis. In addition, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used the STRING database to characterize protein-protein interaction network. RESULTS: Using the same algorithm based on the Rotterdam criteria, we identified 2995 patients with polycystic ovary syndrome and 53,599 population controls in total (2742 cases and 51,438 controls from the discovery phase; 253 cases and 2161 controls in the validation phase). We identified 1 novel genome-wide significant variant rs17186366 (odds ratio [OR]=1.37 [1.23, 1.54], P=2.8×10-8) located near SOD2. In addition, 2 loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42, 2.10], P=5.2×10-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52, 2.86], P=8.45×10-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 single-nucleotide polymorphisms with each criterion in the polycystic ovary syndrome algorithm, we found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, whereas rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. We also validated the previously reported association with DENND1A1. Using the STRING database to characterize protein-protein interactions, we found both ERBB4 and WWTR1 can interact with YAP1, which has been previously associated with polycystic ovary syndrome. CONCLUSION: Through a discovery-validation genome-wide association study on polycystic ovary syndrome identified from electronic health records using an algorithm based on Rotterdam criteria, we identified and validated a novel genome-wide significant association with a variant near SOD2. We also identified a novel independent variant within ERBB4 and a suggestive association with WWTR1. With previously identified polycystic ovary syndrome gene YAP1, the ERBB4-YAP1-WWTR1 network suggests involvement of the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of polycystic ovary syndrome.

Usefulness of Predischarge Cardiac Testing in Low Risk Women and Men for Safe, Rapid Discharge from a Chest Pain Unit.

Predischarge cardiac testing (PDT) in low-risk patients evaluated for acute coronary syndrome in a chest pain unit (CPU) remains a challenge. It is unclear whether PDT varies by gender. We analyzed consecutive low-risk women and men evaluated in our CPU over a 2-year period and compared the utilization of PDT (exercise treadmill test, myocardial stress perfusion scintigraphy, exercise stress echocardiography, invasive coronary angiography, or no test), and incidence of major adverse cardiac events (MACE) at 30 days and 6 months. The study group comprised 619 patients (54% women). A large proportion of both genders did not undergo PDT, although this finding was more frequent in women (50% women vs 40% men, p = 0.01). At 30 days, there were no MACE in either gender. After 6 months of follow-up, MACE remained very low in both women and men (2 [1%] vs 2 [1%]), and in patients who did and did not receive PDT (2 [1%] vs 2 [1%]). Mean length of stay in the CPU was 5.4 hours in patients without PDT and 9.8 hours in those with PDT (p <0.0001) without altering postdischarge MACE. When referred for PDT, women more often underwent myocardial stress perfusion scintigraphy than men (22% vs 14%, p = 0.005) and less often received exercise treadmill test (20% vs 39%, p <0.0001). Yield of abnormal PDT was low in both women and men although it was lower in women (1% vs 5%, p = 0.02). In conclusion, many low-risk women and men evaluated in a CPU for acute coronary syndrome can be safely and rapidly discharged without PDT and with low risk for MACE at 30 days and at 6 months. Exclusion of PDT was associated with significantly reduced length of stay while maintaining safety in terms of postdischarge MACE.

Healthcare Utilization and Patients' Perspectives After Receiving a Positive Genetic Test for Familial Hypercholesterolemia.

BACKGROUND: The MyCode Community Health Initiative (MyCode) is returning actionable results from whole exome sequencing. Familial hypercholesterolemia (FH) is an inherited condition characterized by premature cardiovascular disease. METHODS: We used multiple methods to assess care in 28 MyCode participants who received FH results. Chart reviews were conducted on 23 individuals in the sample and 7 individuals participated semistructured interviews. RESULTS: Chart reviews for 23 individuals with a Geisinger primary care provider found that 4 individuals (17% of 23) were at LDL-C (low-density lipoprotein cholesterol) goal (of either LDL-C <100 mg/dL for primary prevention and LDL-C <70 mg/dL for secondary prevention) and 17 individuals (74% of 23) were prescribed lipid-lowering therapy before genetic result disclosure. After disclosure of the genetic test result, 5 individuals (22% of 23) met their LDL-C goal and 18 individuals (78% of 23) were prescribed lipid-lowering therapy. Follow-up care about this result was not documented for 4 individuals (17% of 23). Changes to intensity of medication management were made for 8 individuals (47% of 17 individuals previously prescribed lipid-lowering therapy). Interviewed individuals (n=7) were not surprised by their result as all knew they had high cholesterol; however, individuals did not seem to discern FH as a separate condition from their high cholesterol. CONCLUSIONS: Among individuals receiving genetic diagnosis of FH, >25% had no changes to lipid-lowering therapy, despite not being at LDL-C goal and learning their high cholesterol is related to a genetic condition requiring more aggressive treatment. Individuals and clinicians may have an inadequate understanding of FH as a distinct condition requiring enhanced medical management.

Strategies to improve stimulation efficiency for retinal prostheses.

Retinitis Pigmentosa (RP) is a degenerative disease of the retina that leads to vision loss. Retinal prostheses are being developed in order to restore functional vision in patients suffering from RP. We conducted in-vivo experiments in order to identify strategies to efficiently stimulate the retina. We electrically stimulated the retina and measured electrically evoked potentials (EERs) from the superior colliculus of rats. We compared the strength of EERs when voltage-controlled and current-controlled pulses of varying pulse width and charge levels were applied to the retina. In addition to comparing EER strength, we evaluated improvement in power efficiency afforded by a high surface area platinum-iridium material. Voltage-controlled pulses were more efficient than current-controlled pulses when the pulses have a short duration (<; 1 ms) and current-controlled pulses were more efficient than voltage-controlled pulses when the pulse width was greater than 1 ms. The high surface area platinum-iridium stimulation electrode consumed power significantly lower than a standard platinum-iridium electrode.

Time-varying pulse trains limit retinal desensitization caused by continuous electrical stimulation.

An epiretinal prosthesis aims to restore functional vision in patients suffering from retinal degeneration caused by diseases such as Retinitis Pigmentosa (RP) and Age-Related Macular Degeneration (AMD). These diseases result in the loss of photoreceptors but bipolar, amacrine and ganglion cells survive at high rates and can be electrically activate to produce the sensation of light. Continuous application of biphasic stimulus pulses results in desensitization of the retina. In humans, this manifests as decreased brightness and increased stimulus thresholds. This study presents an in vivo model of retinal desensitization caused by continuous electrical stimulation and describes a novel stimulation pattern that limit desensitization.