Publications by authors named "Jennifer E Below"

72 Publications

Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues.

Hum Mol Genet 2021 Nov 12. Epub 2021 Nov 12.

LIFE Research Center of Civilization Diseases, University of Leipzig, Leipzig, Germany.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent genome-wide association study on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD, and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL, and TLN2 as new candidate genes whose differential expression might modulate cIMT.
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http://dx.doi.org/10.1093/hmg/ddab236DOI Listing
November 2021

Gut Microbiome Features Associated with Liver Fibrosis in Hispanics, a Population at High Risk for Fatty Liver Disease.

Hepatology 2021 Oct 11. Epub 2021 Oct 11.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background And Aims: Hispanics are disproportionately affected by non-alcoholic fatty liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Preventive strategies and non-invasive means to identify those in this population at high risk for liver fibrosis, are urgently needed. We aimed to characterize the gut microbiome signatures and related biological functions associated with liver fibrosis in Hispanics and identify environmental and genetic factors affecting them.

Approach And Results: Subjects of the population-based Cameron County Hispanic Cohort (n=217) were screened by vibration-controlled transient elastography (FibroScan). Among them, 144 (66.7%) had steatosis and 28 (13.0%) had liver fibrosis. The gut microbiome of subjects with liver fibrosis was enriched with immunogenic commensals (e.g. Prevotella copri, Holdemanella, Clostridiaceae 1) and depleted of Bacteroides caccae, Parabacteroides distasonis, Enterobacter and Marinifilaceae. The liver fibrosis-associated metagenome was characterized by changes in the urea cycle, L-citrulline biosynthesis and creatinine degradation pathways, and altered synthesis of B vitamins and lipoic acid. These metagenomic changes strongly correlated with the depletion of Parabacteroides distasonis and enrichment of Prevotella and Holdemanella. Liver fibrosis was also associated with depletion of bacterial pathways related to L-fucose biosynthesis. Alcohol consumption, even moderate, was associated with high Prevotella abundance. The single nucleotide polymorphisms rs3769502 and rs7573751 in the NCK2 gene positively associated with high Prevotella abundance.

Conclusion: Hispanics with liver fibrosis display microbiome profiles and associated functional changes that may promote oxidative stress and a pro-inflammatory environment. These microbiome signatures, together with NCK2 polymorphisms, may have utility in risk modeling and disease prevention in this high-risk population.
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http://dx.doi.org/10.1002/hep.32197DOI Listing
October 2021

Genetic discovery and risk characterization in type 2 diabetes across diverse populations.

HGG Adv 2021 Apr 9;2(2). Epub 2021 Mar 9.

Division of Statistical Genomics, School of Medicine, Washington University, St. Louis, MO, USA.

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p = 2.06 × 10), which replicated in independent studies of African ancestry (p = 6.26 × 10). We identified a multiethnic risk variant in the gene (rs13052926, RAF = 14.1%, OR = 1.08, p = 5.75 × 10), which also replicated in independent studies (p = 3.45 × 10). We also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (p = 3.85 × 10). Comparing individuals in the top GRS risk category (40%-60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.
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http://dx.doi.org/10.1016/j.xhgg.2021.100029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486151PMC
April 2021

Genome-wide association study of body fat distribution traits in Hispanics/Latinos from the HCHS/SOL.

Hum Mol Genet 2021 Nov;30(22):2190-2204

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA 91101, USA.

Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify the loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC) and hip circumference (HIP) adjusted for body mass index (adjBMI) by using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban and Dominican) background residing in the USA. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for waist-to-hip ratio adjusted for body mass index (WHRadjBMI), 22 for waist circumference adjusted for body mass index (WCadjBMI) and 28 for hip circumference adjusted for body mass index (HIPadjBMI), which reached suggestive significance (P < 1 × 10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (P < 0.05 and consistent direction of effect, and P < 5 × 10-8 after meta-analysis), including two for WHRadjBMI (rs13301996, rs79478137); one for WCadjBMI (rs3168072) and one for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI, 10 for WCadjBMI and 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity susceptibility that may be ancestry-specific.
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http://dx.doi.org/10.1093/hmg/ddab166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561424PMC
November 2021

Revisiting Some Useful Statistical Guidelines in in Response to a Changing Landscape.

Circ Res 2021 May 25;128(11):1724-1727. Epub 2021 May 25.

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN (J.B.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202354PMC
May 2021

Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report From the American Heart Association.

Circulation 2021 Jul 25;144(4):e70-e91. Epub 2021 May 25.

Department of Cardiovascular Diseases Medicine, Mayo Clinic College of Medicine, Rochester, MN (V.L.R.).

Statistical analyses are a crucial component of the biomedical research process and are necessary to draw inferences from biomedical research data. The application of sound statistical methodology is a prerequisite for publication in the American Heart Association (AHA) journal portfolio. The objective of this document is to summarize key aspects of statistical reporting that might be most relevant to the authors, reviewers, and readership of AHA journals. The AHA Scientific Publication Committee convened a task force to inventory existing statistical standards for publication in biomedical journals and to identify approaches suitable for the AHA journal portfolio. The experts on the task force were selected by the AHA Scientific Publication Committee, who identified 12 key topics that serve as the section headers for this document. For each topic, the members of the writing group identified relevant references and evaluated them as a resource to make the standards summarized herein. Each section was independently reviewed by an expert reviewer who was not part of the task force. Expert reviewers were also permitted to comment on other sections if they chose. Differences of opinion were adjudicated by consensus. The standards presented in this report are intended to serve as a guide for high-quality reporting of statistical analyses methods and results.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055393DOI Listing
July 2021

Identifying developmental stuttering and associated comorbidities in electronic health records and creating a phenome risk classifier.

J Fluency Disord 2021 06 15;68:105847. Epub 2021 Apr 15.

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, United States. Electronic address:

Purpose: This study aimed to identify cases of developmental stuttering and associated comorbidities in de-identified electronic health records (EHRs) at Vanderbilt University Medical Center, and, in turn, build and test a stuttering prediction model.

Methods: A multi-step process including a keyword search of medical notes, a text-mining algorithm, and manual review was employed to identify stuttering cases in the EHR. Confirmed cases were compared to matched controls in a phenotype code (phecode) enrichment analysis to reveal conditions associated with stuttering (i.e., comorbidities). These associated phenotypes were used as proxy variables to phenotypically predict stuttering in subjects within the EHR that were not otherwise identifiable using the multi-step identification process described above.

Results: The multi-step process resulted in the manually reviewed identification of 1,143 stuttering cases in the EHR. Highly enriched phecodes included codes related to childhood onset fluency disorder, adult-onset fluency disorder, hearing loss, sleep disorders, atopy, a multitude of codes for infections, neurological deficits, and body weight. These phecodes were used as variables to create a phenome risk classifier (PheRC) prediction model to identify additional high likelihood stuttering cases. The PheRC prediction model resulted in a positive predictive value of 83 %.

Conclusions: This study demonstrates the feasibility of using EHRs in the study of stuttering and found phenotypic associations. The creation of the PheRC has the potential to enable future studies of stuttering using existing EHR data, including investigations into the genetic etiology.
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http://dx.doi.org/10.1016/j.jfludis.2021.105847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188400PMC
June 2021

Pedigree reconstruction and distant pairwise relatedness estimation from genome sequence data: A demonstration in a population of rhesus macaques (Macaca mulatta).

Mol Ecol Resour 2021 May 27;21(4):1333-1346. Epub 2021 Jan 27.

Vanderbilt Genetics Institute and Department of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

A primary challenge in the analysis of free-ranging animal populations is the accurate estimation of relatedness among individuals. Many aspects of population analysis rely on knowledge of relatedness patterns, including socioecology, demography, heritability and gene mapping analyses, wildlife conservation and the management of breeding colonies. Methods for determining relatedness using genome-wide data have improved our ability to determine kinship and reconstruct pedigrees in humans. However, methods for reconstructing complex pedigree structures and estimating distant relatedness (beyond third-degree) have not been widely applied to other species. We sequenced the genomes of 150 male rhesus macaques from the Tulane National Primate Research Center colony to estimate pairwise relatedness, reconstruct closely related pedigrees, estimate more distant relationships and augment colony records. Methods for determining relatedness developed for human genetic data were applied and evaluated in the analysis of nonhuman primates, including identity-by-descent-based methods for pedigree reconstruction and shared segment-based inference of more distant relatedness. We compared the genotype-based pedigrees and estimated relationships to available colony pedigree records and found high concordance (95.5% agreement) between expected and identified relationships for close relatives. In addition, we detected distant relationships not captured in colony records, including some as distant as twelfth-degree. Furthermore, while deep sequence coverage is preferable, we show that this approach can also provide valuable information when only low-coverage (5×) sequence data is available. Our findings demonstrate the value of these methods for determination of relatedness in various animal populations, with diverse applications to conservation biology, evolutionary and ecological research and biomedical studies.
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http://dx.doi.org/10.1111/1755-0998.13317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247968PMC
May 2021

Host genetic effects in pneumonia.

Am J Hum Genet 2021 01 13;108(1):194-201. Epub 2020 Dec 13.

Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address:

Given the coronavirus disease 2019 (COVID-19) pandemic, investigations into host susceptibility to infectious diseases and downstream sequelae have never been more relevant. Pneumonia is a lung disease that can cause respiratory failure and hypoxia and is a common complication of infectious diseases, including COVID-19. Few genome-wide association studies (GWASs) of host susceptibility and severity of pneumonia have been conducted. We performed GWASs of pneumonia susceptibility and severity in the Vanderbilt University biobank (BioVU) with linked electronic health records (EHRs), including Illumina Expanded Multi-Ethnic Global Array (MEGA)-genotyped European ancestry (EA, n= 69,819) and African ancestry (AA, n = 15,603) individuals. Two regions of large effect were identified: the CFTR locus in EA (rs113827944; OR = 1.84, p value = 1.2 × 10) and HBB in AA (rs334 [p.Glu7Val]; OR = 1.63, p value = 3.5 × 10). Mutations in these genes cause cystic fibrosis (CF) and sickle cell disease (SCD), respectively. After removing individuals diagnosed with CF and SCD, we assessed heterozygosity effects at our lead variants. Further GWASs after removing individuals with CF uncovered an additional association in R3HCC1L (rs10786398; OR = 1.22, p value = 3.5 × 10), which was replicated in two independent datasets: UK Biobank (n = 459,741) and 7,985 non-overlapping BioVU subjects, who are genotyped on arrays other than MEGA. This variant was also validated in GWASs of COVID-19 hospitalization and lung function. Our results highlight the importance of the host genome in infectious disease susceptibility and severity and offer crucial insight into genetic effects that could potentially influence severity of COVID-19 sequelae.
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http://dx.doi.org/10.1016/j.ajhg.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820802PMC
January 2021

Optimizing Genetic Analyses of Serum Lipids in Longitudinal Data.

Circ Res 2020 10 2;127(10):1337-1339. Epub 2020 Sep 2.

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, (H.-H.C., L.E.P., E.R.G., Q.S.W., J.E.B.), Vanderbilt University Medical Center, Nashville, TN.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581558PMC
October 2020

Automated Phenotyping Tool for Identifying Developmental Language Disorder Cases in Health Systems Data (APT-DLD): A New Research Algorithm for Deployment in Large-Scale Electronic Health Record Systems.

J Speech Lang Hear Res 2020 09 11;63(9):3019-3035. Epub 2020 Aug 11.

Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN.

Purpose Data mining algorithms using electronic health records (EHRs) are useful in large-scale population-wide studies to classify etiology and comorbidities (Casey et al., 2016). Here, we apply this approach to developmental language disorder (DLD), a prevalent communication disorder whose risk factors and epidemiology remain largely undiscovered. Method We first created a reliable system for manually identifying DLD in EHRs based on speech-language pathologist (SLP) diagnostic expertise. We then developed and validated an automated algorithmic procedure, called, Automated Phenotyping Tool for identifying DLD cases in health systems data (APT-DLD), that classifies a DLD status for patients within EHRs on the basis of ICD (International Statistical Classification of Diseases and Related Health Problems) codes. APT-DLD was validated in a discovery sample ( = 973) using expert SLP manual phenotype coding as a gold-standard comparison and then applied and further validated in a replication sample of = 13,652 EHRs. Results In the discovery sample, the APT-DLD algorithm correctly classified 98% (concordance) of DLD cases in concordance with manually coded records in the training set, indicating that APT-DLD successfully mimics a comprehensive chart review. The output of APT-DLD was also validated in relation to independently conducted SLP clinician coding in a subset of records, with a positive predictive value of 95% of cases correctly classified as DLD. We also applied APT-DLD to the replication sample, where it achieved a positive predictive value of 90% in relation to SLP clinician classification of DLD. Conclusions APT-DLD is a reliable, valid, and scalable tool for identifying DLD cohorts in EHRs. This new method has promising public health implications for future large-scale epidemiological investigations of DLD and may inform EHR data mining algorithms for other communication disorders. Supplemental Material https://doi.org/10.23641/asha.12753578.
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http://dx.doi.org/10.1044/2020_JSLHR-19-00397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890229PMC
September 2020

Alternative Applications of Genotyping Array Data Using Multivariant Methods.

Trends Genet 2020 11 6;36(11):857-867. Epub 2020 Aug 6.

Department of Internal Medicine, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87109, USA. Electronic address:

One of the forerunners that pioneered the revolution of high-throughput genomic technologies is the genotyping microarray technology, which can genotype millions of single-nucleotide variants simultaneously. Owing to apparent benefits, such as high speed, low cost, and high throughput, the genotyping array has gained lasting applications in genome-wide association studies (GWAS) and thus accumulated an enormous amount of data. Empowered by continuous manufactural upgrades and analytical innovation, unconventional applications of genotyping array data have emerged to address more diverse genetic problems, holding promise of boosting genetic research into human diseases through the re-mining of the rich accumulated data. Here, we review several unconventional genotyping array analysis techniques that have been built on the idea of large-scale multivariant analysis and provide empirical application examples. These unconventional outcomes of genotyping arrays include polygenic score, runs of homozygosity (ROH)/heterozygosity ratio, distant pedigree computation, and mitochondrial DNA (mtDNA) copy number inference.
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http://dx.doi.org/10.1016/j.tig.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572808PMC
November 2020

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Nature 2020 06 6;582(7811):240-245. Epub 2020 May 6.

Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D); however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
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http://dx.doi.org/10.1038/s41586-020-2263-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292783PMC
June 2020

Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations.

Circ Res 2020 06 4;126(12):1816-1840. Epub 2020 Jun 4.

Department of Epidemiology, Gillings School of Global Public Health (K.L.Y, H.M.H., C.A., S.-A.M.L., M.G., K.D., K.E.N.), University of North Carolina at Chapel Hill.

Genome-wide association studies have revolutionized our understanding of the genetic underpinnings of cardiometabolic disease. Yet, the inadequate representation of individuals of diverse ancestral backgrounds in these studies may undercut their ultimate potential for both public health and precision medicine. The goal of this review is to describe the imperativeness of studying the populations who are most affected by cardiometabolic disease, to the aim of better understanding the genetic underpinnings of the disease. We support this premise by describing the current variation in the global burden of cardiometabolic disease and emphasize the importance of building a globally and ancestrally representative genetics evidence base for the identification of population-specific variants, fine-mapping, and polygenic risk score estimation. We discuss the important ethical, legal, and social implications of increasing ancestral diversity in genetic studies of cardiometabolic disease and the challenges that arise from the (1) lack of diversity in current reference populations and available analytic samples and the (2) unequal generation of health-associated genomic data and their prediction accuracies. Despite these challenges, we conclude that additional, unprecedented opportunities lie ahead for public health genomics and the realization of precision medicine, provided that the gap in diversity can be systematically addressed. Achieving this goal will require concerted efforts by social, academic, professional and regulatory stakeholders and communities, and these efforts must be based on principles of equity and social justice.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285892PMC
June 2020

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

PLoS Genet 2020 03 30;16(3):e1008684. Epub 2020 Mar 30.

Department of Medicine, University of Washington Medical Center, Seattle, Washington, United States of America.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.
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http://dx.doi.org/10.1371/journal.pgen.1008684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145272PMC
March 2020

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.

Hum Mutat 2020 02 25;41(2):487-501. Epub 2019 Nov 25.

Department of Neurology, Program in Neurogenetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.
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http://dx.doi.org/10.1002/humu.23946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182470PMC
February 2020

GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations.

PLoS One 2019 28;14(6):e0217796. Epub 2019 Jun 28.

Cardiovascular Health Research Unit, University of Washington, Seattle, WA, United States of America.

Background: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.

Methods: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.

Results: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.

Conclusions: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217796PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599128PMC
February 2020

A Genome-Wide Association Study Identifies Blood Disorder-Related Variants Influencing Hemoglobin A With Implications for Glycemic Status in U.S. Hispanics/Latinos.

Diabetes Care 2019 09 18;42(9):1784-1791. Epub 2019 Jun 18.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY

Objective: We aimed to identify hemoglobin A (HbA)-associated genetic variants and examine their implications for glycemic status evaluated by HbA in U.S. Hispanics/Latinos with diverse genetic ancestries.

Research Design And Methods: We conducted a genome-wide association study (GWAS) of HbA in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies.

Results: Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA at genome-wide significance levels ( < 5.0 × 10). In particular, two African ancestry-specific variants, rs334 and -rs1050828, which are causal mutations for sickle cell disease and deficiency, respectively, had ∼10 times larger effect sizes on HbA levels (β = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, -rs145546625, was associated with HbA and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of rs334 or -rs1050828 HbA-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, < 0.001). After recalibration of the HbA level taking -rs334 and -rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, = 0.28).

Conclusions: This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA test is performed.
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http://dx.doi.org/10.2337/dc19-0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702612PMC
September 2019

My Cousin Also Has Atrial Fibrillation: Family Relationships in a Genomic Era.

JACC Clin Electrophysiol 2019 04;5(4):501-503

Vanderbilt Genetics Institute and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.

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http://dx.doi.org/10.1016/j.jacep.2019.03.002DOI Listing
April 2019

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.

PLoS Genet 2019 04 16;15(4):e1007739. Epub 2019 Apr 16.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, United States of America.

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.
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http://dx.doi.org/10.1371/journal.pgen.1007739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467367PMC
April 2019

GWAS and Beyond: Using Omics Approaches to Interpret SNP Associations.

Curr Genet Med Rep 2019 Mar 14;7(1):30-40. Epub 2019 Feb 14.

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Purpose Of Review: Neurodegenerative diseases, neuropsychiatric disorders, and related traits have highly complex etiologies but are also highly heritable and identifying the causal genes and biological pathways underlying these traits may advance the development of treatments and preventive strategies. While many genome-wide association studies (GWAS) have successfully identified variants contributing to polygenic neurodegenerative and neuropsychiatric phenotypes including Alzheimer's disease (AD), schizophrenia (SCZ), and bipolar disorder (BPD) amongst others, interpreting the biological roles of significantly-associated variants in the genetic architecture of these traits remains a significant challenge. Here we review several 'omics' approaches which attempt to bridge the gap from associated genetic variants to phenotype by helping define the functional roles of GWAS loci in the development of neuropsychiatric disorders and traits.

Recent Findings: Several common 'omics' approaches have been applied to examine neuropsychiatric traits, such as nearest-gene mapping, trans-ethnic fine mapping, annotation enrichment analysis, transcriptomic analysis, and pathway analysis, and each of these approaches has strengths and limitations in providing insight into biological mechanisms. One popular emerging method is the examination of tissue-specific genetically-regulated gene expression (GReX), which aggregates the genetic variants' effects at the gene-level. Furthermore, proteomic, metabolomic, and microbiomic studies and phenome-wide association studies will further enhance our understanding of neuropsychiatric traits.

Summary: GWAS has been applied to neuropsychiatric traits for a decade, but our understanding about the biological function of identified variants remains limited. Today, technological advancements have created analytical approaches for integrating transcriptomics, metabolomics, proteomics, pharmacology and toxicology as tools for understanding the functional roles of genetics variants. These data, as well as the broader clinical information provided by electronic health records, can provide additional insight and complement genomic analyses.
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http://dx.doi.org/10.1007/s40142-019-0159-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731888PMC
March 2019

Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample.

Hum Mol Genet 2019 04;28(7):1212-1224

Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.

Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-ancestry and African-ancestry populations and identified substantial predictive power using European-derived models in a non-European target population. We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset.
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http://dx.doi.org/10.1093/hmg/ddy435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423424PMC
April 2019

Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans.

Hum Mol Genet 2019 02;28(4):675-687

Physiology and Biophysics, University of Mississippi, Jackson, MS, USA.

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.
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http://dx.doi.org/10.1093/hmg/ddy387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360325PMC
February 2019

Complex patterns of direct and indirect association between the transcription Factor-7 like 2 gene, body mass index and type 2 diabetes diagnosis in adulthood in the Hispanic Community Health Study/Study of Latinos.

BMC Obes 2018 2;5:26. Epub 2018 Oct 2.

1Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 123 W Franklin St, Building C, Chapel Hill, NC USA.

Background: Genome-wide association studies have implicated the () gene in type 2 diabetes risk, and more recently, in decreased body mass index. Given the contrary direction of genetic effects on these two traits, it has been suggested that the observed association with body mass index may reflect either selection bias or a complex underlying biology at .

Methods: Using 9031 Hispanic/Latino adults (21-76 years) with complete weight history and genetic data from the community-based Hispanic Community Health Study/Study of Latinos (HCHS/SOL, Baseline 2008-2011), we estimated the multivariable association between the additive number of type 2 diabetes increasing-alleles at (rs7903146-T) and body mass index. We then used structural equation models to simultaneously model the genetic association on changes in body mass index across the life course and estimate the odds of type 2 diabetes per risk allele.

Results: We observed both significant increases in type 2 diabetes prevalence at examination (independent of body mass index) and decreases in mean body mass index and waist circumference across genotypes at rs7903146. We observed a significant multivariable association between the additive number of type 2 diabetes-risk alleles and lower body mass index at examination. In our structured modeling, we observed non-significant inverse direct associations between rs7903146-T and body mass index at ages 21 and 45 years, and a significant positive association between rs7903146-T and type 2 diabetes onset in both middle and late adulthood.

Conclusions: Herein, we replicated the protective effect of rs7930146-T on body mass index at multiple time points in the life course, and observed that these effects were not explained by past type 2 diabetes status in our structured modeling. The robust replication of the negative effects of on body mass index in multiple samples, including in our diverse Hispanic/Latino community-based sample, supports a growing body of literature on the complex biologic mechanism underlying the functional consequences of on obesity and type 2 diabetes across the life course.
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http://dx.doi.org/10.1186/s40608-018-0200-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167893PMC
October 2018

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.

Nat Genet 2018 11 8;50(11):1505-1513. Epub 2018 Oct 8.

Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
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http://dx.doi.org/10.1038/s41588-018-0241-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287706PMC
November 2018

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

Mol Psychiatry 2020 08 14;25(8):1859-1875. Epub 2018 Aug 14.

McDonnell Genome Institute, Washington University, St. Louis, MO, USA.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
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http://dx.doi.org/10.1038/s41380-018-0112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375806PMC
August 2020

Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.

Hum Genet 2018 Sep 26;137(9):689-703. Epub 2018 Jul 26.

Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Millet Cad., Capa, Fatih, 34093, Istanbul, Turkey.

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM #614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and BCOR (Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.
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http://dx.doi.org/10.1007/s00439-018-1907-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165673PMC
September 2018

Critical Evaluation of Data Requires Rigorous but Broadly Based Statistical Inference.

Circ Res 2018 04;122(8):1049-1051

From the Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN.

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http://dx.doi.org/10.1161/CIRCRESAHA.118.312530DOI Listing
April 2018

Expanding the global prevalence of spinocerebellar ataxia type 42.

Neurol Genet 2018 Jun 5;4(3):e232. Epub 2018 Apr 5.

Department of Neurology (K.J.N., M.A., S.P., G.C., B.L.F.), Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles; Department of Medical Genetics (L.E.P., J.E.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Psychiatry and Biobehavioral Sciences (J.A.C., G.C.), University of California, Los Angeles, CA; Institute of Neurological Sciences (F.C., S.C.), Italian National Research Council, Mangone, Italy; Department of Neurology (A.B.N., M.D.G.), UCSF Memory and Aging Center, University of California, San Francisco; Sackler Faculty of Medicine (S.H.), Tel-Aviv University, Israel; Italian College of General Practitioners and Primary Care (D.I.), Department of Clinical and Experimental Medicine (A.L.), University of Messina, Italy; and the Department of Human Genetics (B.L.F.), David Geffen School of Medicine, University of California, Los Angeles.

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http://dx.doi.org/10.1212/NXG.0000000000000232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886831PMC
June 2018
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