Autism Speaks' Autism Genetic Resource Exchange (AGRE) represents the largest private collection of genetic and phenotype data for families with ASD that is made available to qualified researchers ...worldwide. The availability of large and comprehensive registries that include detailed phenotype and genetic information for individuals affected with an ASD and family members is crucial for the discovery of autism susceptibility genes and the development and application of biologically based approaches to diagnosis and treatment. The model that AGRE has developed can be applied broadly to other disorders with complex etiologies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Obtaining explicit consent from patients to use their remnant biological samples and deidentified clinical data for research is essential for advancing precision medicine.
We aimed to describe the ...operational implementation and scalability of an electronic universal consent process that was used to power an institutional precision health biobank across a large academic health system.
The University of California, Los Angeles, implemented the use of innovative electronic consent videos as the primary recruitment tool for precision health research. The consent videos targeted patients aged ≥18 years across ambulatory clinical laboratories, perioperative settings, and hospital settings. Each of these major areas had slightly different workflows and patient populations. Sociodemographic information, comorbidity data, health utilization data (ambulatory visits, emergency room visits, and hospital admissions), and consent decision data were collected.
The consenting approach proved scalable across 22 clinical sites (hospital and ambulatory settings). Over 40,000 participants completed the consent process at a rate of 800 to 1000 patients per week over a 2-year time period. Participants were representative of the adult University of California, Los Angeles, Health population. The opt-in rates in the perioperative (16,500/22,519, 73.3%) and ambulatory clinics (2308/3390, 68.1%) were higher than those in clinical laboratories (7506/14,235, 52.7%; P<.001). Patients with higher medical acuity were more likely to opt in. The multivariate analyses showed that African American (odds ratio OR 0.53, 95% CI 0.49-0.58; P<.001), Asian (OR 0.72, 95% CI 0.68-0.77; P<.001), and multiple-race populations (OR 0.73, 95% CI 0.69-0.77; P<.001) were less likely to participate than White individuals.
This is one of the few large-scale, electronic video-based consent implementation programs that reports a 65.5% (26,314/40,144) average overall opt-in rate across a large academic health system. This rate is higher than those previously reported for email (3.6%) and electronic biobank (50%) informed consent rates. This study demonstrates a scalable recruitment approach for population health research.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Autism is among the most clearly genetically determined of all cognitive-developmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from ...the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: a small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Large medical centers in urban areas, like Los Angeles, care for a diverse patient population and offer the potential to study the interplay between genetic ancestry and social determinants of ...health. Here, we explore the implications of genetic ancestry within the University of California, Los Angeles (UCLA) ATLAS Community Health Initiative-an ancestrally diverse biobank of genomic data linked with de-identified electronic health records (EHRs) of UCLA Health patients (N=36,736).
We quantify the extensive continental and subcontinental genetic diversity within the ATLAS data through principal component analysis, identity-by-descent, and genetic admixture. We assess the relationship between genetically inferred ancestry (GIA) and >1500 EHR-derived phenotypes (phecodes). Finally, we demonstrate the utility of genetic data linked with EHR to perform ancestry-specific and multi-ancestry genome and phenome-wide scans across a broad set of disease phenotypes.
We identify 5 continental-scale GIA clusters including European American (EA), African American (AA), Hispanic Latino American (HL), South Asian American (SAA) and East Asian American (EAA) individuals and 7 subcontinental GIA clusters within the EAA GIA corresponding to Chinese American, Vietnamese American, and Japanese American individuals. Although we broadly find that self-identified race/ethnicity (SIRE) is highly correlated with GIA, we still observe marked differences between the two, emphasizing that the populations defined by these two criteria are not analogous. We find a total of 259 significant associations between continental GIA and phecodes even after accounting for individuals' SIRE, demonstrating that for some phenotypes, GIA provides information not already captured by SIRE. GWAS identifies significant associations for liver disease in the 22q13.31 locus across the HL and EAA GIA groups (HL p-value=2.32×10
, EAA p-value=6.73×10
). A subsequent PheWAS at the top SNP reveals significant associations with neurologic and neoplastic phenotypes specifically within the HL GIA group.
Overall, our results explore the interplay between SIRE and GIA within a disease context and underscore the utility of studying the genomes of diverse individuals through biobank-scale genotyping linked with EHR-based phenotyping.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Introduction Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin ...study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently. Methods Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed. Results Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27–3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12–4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04–3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28–6.74). Conclusions Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The UCLA ATLAS Community Health Initiative (ATLAS) has an initial target to recruit 150,000 participants from across the UCLA Health system with the goal of creating a genomic database to accelerate ...precision medicine efforts in California. This initiative includes a biobank embedded within the UCLA Health system that comprises de-identified genomic data linked to electronic health records (EHRs). The first freeze of data from September 2020 contains 27,987 genotyped samples imputed to 7.9 million SNPs across the genome and is linked with de-identified versions of the EHRs from UCLA Health. Here, we describe a centralized repository of the genotype data and provide tools and pipelines to perform genome- and phenome-wide association studies across a wide range of EHR-derived phenotypes and genetic ancestry groups. We demonstrate the utility of this resource through the analysis of 7 well-studied traits and recapitulate many previous genetic and phenotypic associations.
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•UCLA ATLAS Community Health Initiative aims to genotype 150,000 participants•Electronic health record information is linked to participants’ genotype data•5 major continental genetic ancestry groups are represented in ATLAS•GWAS and PheWAS recapitulate known associations and offer insights into disease risk
Johnson et al. describe the UCLA ATLAS Community Health Initiative (ATLAS), which aims to recruit 150,000 participants from across the UCLA Health system and create one of the largest genomic databases linked to electronic health records. They describe the extensive ancestral diversity of the ATLAS cohort and demonstrate its utility as a biomedical resource for understanding the genetic basis of disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Developing innovative, efficient, and institutionally scalable biospecimen consent for remnant tissue that meets the National Institutes of Health consent guidelines for genomic and molecular ...analysis is essential for precision medicine efforts in cancer.
This study aims to pilot-test an electronic video consent that individuals could complete largely on their own.
The University of California, Los Angeles developed a video consenting approach designed to be comprehensive yet fast (around 5 minutes) for providing universal consent for remnant biospecimen collection for research. The approach was piloted in 175 patients who were coming in for routine services in laboratory medicine, radiology, oncology, and hospital admissions. The pilot yielded 164 completed postconsent surveys. The pilot assessed the usefulness, ease, and trustworthiness of the video consent. In addition, we explored drivers for opting in or opting out.
The pilot demonstrated that the electronic video consent was well received by patients, with high scores for usefulness, ease, and trustworthiness even among patients that opted out of participation. The revised more animated video pilot test in phase 2 was better received in terms of ease of use (P=.005) and the ability to understand the information (P<.001). There were significant differences between those who opted in and opted out in their beliefs concerning the usefulness of tissue, trusting researchers, the importance of contributing to science, and privacy risk (P<.001). The results showed that "I trust researchers to use leftover biological specimens to promote the public's health" and "Sharing a biological sample for research is safe because of the privacy protections in place" discriminated opt-in statuses were the strongest predictors (both areas under the curve were 0.88). Privacy concerns seemed universal in individuals who opted out.
Efforts to better educate the community may be needed to help overcome some of the barriers in engaging individuals to participate in precision health initiatives.
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, ...but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer's disease (AD) is the most common form of dementia and a growing public health burden in the United States. Significant progress has been made in identifying genetic risk for AD, but ...limited studies have investigated how AD genetic risk may be associated with other disease conditions in an unbiased fashion. In this study, we conducted a phenome-wide association study (PheWAS) by genetic ancestry groups within a large academic health system using the polygenic risk score (PRS) for AD. PRS was calculated using LDpred2 with genome-wide association study (GWAS) summary statistics. Phenotypes were extracted from electronic health record (EHR) diagnosis codes and mapped to more clinically meaningful phecodes. Logistic regression with Firth's bias correction was used for PRS phenotype analyses. Mendelian randomization was used to examine causality in significant PheWAS associations. Our results showed a strong association between AD PRS and AD phenotype in European ancestry (OR = 1.26, 95% CI: 1.13, 1.40). Among a total of 1,515 PheWAS tests within the European sample, we observed strong associations of AD PRS with AD and related phenotypes, which include mild cognitive impairment (MCI), memory loss, and dementias. We observed a phenome-wide significant association between AD PRS and gouty arthropathy (OR = 0.90, adjusted
= 0.05). Further causal inference tests with Mendelian randomization showed that gout was not causally associated with AD. We concluded that genetic predisposition of AD was negatively associated with gout, but gout was not a causal risk factor for AD. Our study evaluated AD PRS in a real-world EHR setting and provided evidence that AD PRS may help to identify individuals who are genetically at risk of AD and other related phenotypes. We identified non-neurodegenerative diseases associated with AD PRS, which is essential to understand the genetic architecture of AD and potential side effects of drugs targeting genetic risk factors of AD. Together, these findings expand our understanding of AD genetic and clinical risk factors, which provide a framework for continued research in aging with the growing number of real-world EHR linked with genetic data.
Low income Hispanic families experience multiple barriers to accessing evidence-based information on Autism Spectrum Disorders (ASD). This study utilized a mixed-strategy intervention to create ...access to information in published bio-medical research articles on ASD by distilling the content into parent-friendly English- and Spanish-language ASD Science Briefs and presenting them to participants using two socially-oriented dissemination methods. There was a main effect for short-term knowledge gains associated with the Science Briefs but no effect for the dissemination method. After 5 months, participants reported utilizing the information learned and 90 % wanted to read more Science Briefs. These preliminary findings highlight the potential benefits of distilling biomedical research articles on ASD into parent-friendly educational products for currently underserved Hispanic parents.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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