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1.
Int J Cancer ; 148(1): 99-105, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930425

RESUMO

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

3.
Nat Rev Nephrol ; 16(11): 686-696, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32939051

RESUMO

An important need exists to better understand and stratify kidney disease according to its underlying pathophysiology in order to develop more precise and effective therapeutic agents. National collaborative efforts such as the Kidney Precision Medicine Project are working towards this goal through the collection and integration of large, disparate clinical, biological and imaging data from patients with kidney disease. Ontologies are powerful tools that facilitate these efforts by enabling researchers to organize and make sense of different data elements and the relationships between them. Ontologies are critical to support the types of big data analysis necessary for kidney precision medicine, where heterogeneous clinical, imaging and biopsy data from diverse sources must be combined to define a patient's phenotype. The development of two new ontologies - the Kidney Tissue Atlas Ontology and the Ontology of Precision Medicine and Investigation - will support the creation of the Kidney Tissue Atlas, which aims to provide a comprehensive molecular, cellular and anatomical map of the kidney. These ontologies will improve the annotation of kidney-relevant data, and eventually lead to new definitions of kidney disease in support of precision medicine.

4.
Pharmacoepidemiol Drug Saf ; 29(11): 1393-1401, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32844549

RESUMO

PURPOSE: Computable phenotypes are constructed to utilize data within the electronic health record (EHR) to identify patients with specific characteristics; a necessary step for researching a complex disease state. We developed computable phenotypes for resistant hypertension (RHTN) and stable controlled hypertension (HTN) based on the National Patient-Centered Clinical Research Network (PCORnet) common data model (CDM). The computable phenotypes were validated through manual chart review. METHODS: We adapted and refined existing computable phenotype algorithms for RHTN and stable controlled HTN to the PCORnet CDM in an adult HTN population from the OneFlorida Clinical Research Consortium (2015-2017). Two independent reviewers validated the computable phenotypes through manual chart review of 425 patient records. We assessed precision of our computable phenotypes through positive predictive value (PPV) and test validity through interrater reliability (IRR). RESULTS: Among the 156 730 HTN patients in our final dataset, the final computable phenotype algorithms identified 24 926 patients with RHTN and 19 100 with stable controlled HTN. The PPV for RHTN in patients randomly selected for validation of the final algorithm was 99.1% (n = 113, CI: 95.2%-99.9%). The PPV for stable controlled HTN in patients randomly selected for validation of the final algorithm was 96.5% (n = 113, CI: 91.2%-99.0%). IRR analysis revealed a raw percent agreement of 91% (152/167) with Cohen's kappa statistic = 0.87. CONCLUSIONS: We constructed and validated a RHTN computable phenotype algorithm and a stable controlled HTN computable phenotype algorithm. Both algorithms are based on the PCORnet CDM, allowing for future application to epidemiological and drug utilization based research.

5.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

6.
Pac Symp Biocomput ; 25: 575-586, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31797629

RESUMO

Return of results is not common in research settings as standards are not yet in place for what to return, how to return, and to whom. As a pioneer of large-scale of return of research results, the Precision Medicine Initiative Cohort now known of All of Us plans to return pharmacogenomic results and variants of clinical significance to its participants starting late 2019. To better understand the local landscape of possibilities regarding return of research results, we assessed the frequency of pathogenic variants and APOL1 renal risk variants in a small diverse cohort of chronic kidney disease patients (CKD) ascertained from a public hospital in Cleveland, Ohio genotyped on the Illumina Infinium MegaEX. Of the 23,720 ClinVar-designated variants directly assayed by the MegaEX, 8,355 (35%) had at least one alternate allele in the 130 participants genotyped. Of these, 18 ClinVar variants deemed pathogenic by multiple submitters with no conflicts in interpretation were distributed across 27 participants. The majority of these pathogenic ClinVar variants (14/18) were associated with autosomal recessive disorders. Of note were four African American carriers of TTR rs76992529 associated with amyloidogenic transthyretin amyloidosis, otherwise known as familial transthyretin amyloidosis (FTA). FTA, an autosomal dominant disorder with variable penetrance, is more common among African-descent populations compared with European-descent populations. Also common in this CKD population were APOL1 renal risk alleles G1 (rs73885319) and G2 (rs71785313) with 60% of the study population carrying at least one renal risk allele. Both pathogenic ClinVar variants and APOL1 renal risk alleles were distributed among participants who wanted actionable genetic results returned, wanted genetic results returned regardless of actionability, and wanted no results returned. Results from this local genetic study highlight challenges in which variants to report, how to interpret them, and the participant's potential for follow-up, only some of the challenges in return of research results likely facing larger studies such as All of Us.

7.
Public Health Genomics ; 22(1-2): 16-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31454805

RESUMO

Despite monumental advances in genomics, relatively few health care provider organizations in the United States offer personalized or precision medicine as part of the routine clinical workflow. The gaps between research and applied genomic medicine may be a result of a cultural gap across various stakeholders representing scientists, clinicians, patients, policy makers, and third party payers. Scientists are trained to assess the health care value of genomics by either quantifying population-scale effects, or through the narrow lens of clinical trials where the standard of care is compared with the predictive power of a single or handful of genetic variants. While these metrics are an essential first step in assessing and documenting the clinical utility of genomics, they are rarely followed up with other assessments of health care value that are critical to stakeholders who use different measures to define value. The limited value assessment in both the research and implementation science of precision medicine is likely due to necessary logistical constraints of these teams; engaging bioethicists, health care economists, and individual patient belief systems is incredibly daunting for geneticists and informaticians conducting research. In this narrative review, we concisely describe several definitions of value through various stakeholder viewpoints. We highlight the existing gaps that prevent clinical translation of scientific findings generally as well as more specifically using two present-day, extreme scenarios: (1) genetically guided warfarin dosing representing a handful of genetic markers and more than 10 years of basic and translational research, and (2) next-generation sequencing representing genome-dense data lacking substantial evidence for implementation. These contemporary scenarios highlight the need for various stakeholders to broadly adopt frameworks designed to define and collect multiple value measures across different disciplines to ultimately impact more universal acceptance of and reimbursement for genomic medicine.


Assuntos
Benchmarking/métodos , Pesquisa em Genética , Testes Genéticos , Medicina de Precisão , Pesquisa Médica Translacional/normas , Humanos , Medicina de Precisão/métodos , Medicina de Precisão/normas , Estados Unidos
8.
AMIA Jt Summits Transl Sci Proc ; 2019: 153-162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258967

RESUMO

Electronic health records (EHRs) linked to extensive biorepositories and supplemented with lifestyle, behavioral, and environmental exposure data, have enormous potential to contribute to genomic discovery, a necessary step in the pathway towards translational or precision medicine. A major bottleneck in incorporating EHRs into genomic studies is the extraction of research-grade variables for analysis, particularly when gold-standard measurements are not available or accessible. Here we develop algorithms for age-related macular degeneration (AMD), a common cause of blindness among the elderly, and controls free of AMD. These computable phenotypes were developed using billing codes (ICD-9-CM and ICD-10-CM) and Current Procedural Terminology (CPT) codes and evaluated in two study sites of the Veterans Affairs Million Veteran Program: Louis Stokes Cleveland VA Medical Center and the Providence VA Medical Center. After establishing a high overall positive and negative predictive values (93% and 95%, respectively) through manual chart review, the candidate algorithm was deployed in the full VA MVP dataset of >500,000 participants. The algorithm was then optimized in a data cube using a variety of approaches including adjusting inclusion age thresholds by examining previously-reported genetic associations for CFH (rs10801555, a proxy for rs1061170) and ARMS2 (rs10490924). The algorithm with the smallest p-values for the known genetic associations was selected for downstream and on-going AMD genomic discovery efforts. This two-phase approach to developing research-grade case/control variables for AMD genomic studies capitalizes on established genetic associations resulting in high precision and optimized sample sizes, an approach that can be applied to other large-scale biobanks linked to EHRs for precision medicine research.

9.
Hum Genet ; 138(7): 691-701, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161416

RESUMO

Most genotype-phenotype studies have historically lacked population diversity, impacting the generalizability of findings and thereby limiting the ability to equitably implement precision medicine. This well-documented problem has generated much interest in the ascertainment of new cohorts with an emphasis on multiple dimensions of diversity, including race/ethnicity, gender, age, socioeconomic status, disability, and geography. The most well known of these new cohort efforts is arguably All of Us, formerly known as the Precision Medicine Cohort Initiative Program. All of Us intends to ascertain at least one million participants in the United States representative of the multiple dimensions of diversity. As an incentive to participate, All of Us is offering the return of research results, including whole genome sequencing data, as well as the opportunity to contribute to the scientific process as non-scientists. The scale and scope of the proposed return of research results are unprecedented. Here, we briefly review possible return of genetic data models, including the likely data file formats and modes of data transfer or access. We also review the resources required to access and interpret the genetic or genomic data once received by the average participant, highlighting the nuanced anticipated barriers that will challenge both the digitally, computationally literate and illiterate participant alike. This inventory of resources required to receive, process, and interpret return of research results exposes the potential for access disparities and warns the scientific community to mind the gap so that all participants have equal access and understanding of the benefits of human genetic research.


Assuntos
Interpretação Estatística de Dados , Mineração de Dados/normas , Pesquisa em Genética , Genoma Humano , Genômica/métodos , Medicina de Precisão , Humanos , Estados Unidos
10.
Front Genet ; 10: 428, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134134

RESUMO

African Americans experience the highest burden of hypertension in the United States compared with other groups. Genetic contributions to this complex condition are now emerging in this as well as other populations through large-scale genome-wide association studies (GWAS) and meta-analyses. Despite these recent discovery efforts, relatively few large-scale studies of blood pressure have considered the joint influence of genetics and social determinants of health despite extensive evidence supporting their impact on hypertension. To identify these expected interactions, we accessed a subset of the Vanderbilt University Medical Center (VUMC) biorepository linked to de-identified electronic health records (EHRs) of adult African Americans genotyped using the Illumina Metabochip (n = 2,577). To examine potential interactions between education, a recognized social determinant of health, and genetic variants contributing to blood pressure, we used linear regression models to investigate two-way interactions for systolic and diastolic blood pressure (DBP). We identified a two-way interaction between rs6687976 and education affecting DBP (p = 0.052). Individuals homozygous for the minor allele and having less than a high school education had higher DBP compared with (1) individuals homozygous for the minor allele and high school education or greater and (2) individuals not homozygous for the minor allele and less than a high school education. To our knowledge, this is the first EHR -based study to suggest a gene-environment interaction for blood pressure in African Americans, supporting the hypothesis that genetic contributions to hypertension may be modulated by social factors.

11.
Pac Symp Biocomput ; 24: 220-223, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30864324

RESUMO

For the 2019 Pacific Symposium on Biocomputing's session on precision medicine, we present new research on computational techniques in range of areas including data curation, whole genome analysis, transcriptomics, microbiome profiling, EHR data-mining, and histological image processing.

12.
PLoS One ; 14(12): e0226771, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31891604

RESUMO

We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio-metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p<0.01 in two or more PAGE study sites for two or more phenotype classes. We further annotated these PheWAS-identified variants using publicly available functional data and local genetic ancestry. Amongst our novel findings is SPARC rs4958487, associated with increased glucose levels and hypertension. SPARC has been implicated in the pathogenesis of diabetes and is also known to have a potential role in fibrosis, a common consequence of multiple conditions including hypertension. The SPARC example and others highlight the potential that PheWAS approaches have in improving our understanding of complex disease architecture by identifying novel relationships between genetic variants and an array of common human phenotypes.


Assuntos
Afro-Americanos/genética , Aterosclerose/genética , Pleiotropia Genética , Metagenômica , Fenômica , Idoso , Estudos Epidemiológicos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
13.
Pharmacogenomics J ; 19(3): 295-304, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30237584

RESUMO

Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy-GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10-4 were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES). A genetic risk score for RHTN was created by summing the risk alleles of replicated RHTN signals. rs11749255 in MSX2 was associated with RHTN in INVEST (odds ratio (OR) (95% CI) = 1.50 (1.2-1.8), p = 7.3 × 10-5) and replicated in SPS3 (OR = 2.0 (1.4-2.8), p = 4.3 × 10-5), with genome-wide significance in meta-analysis (OR = 1.60 (1.3-1.9), p = 3.8 × 10-8). Other replicated signals were in IFLTD1 and PTPRD. IFLTD1 rs6487504 was associated with RHTN in INVEST (OR = 1.90 (1.4-2.5), p = 1.1 × 10-5) and SPS3 (OR = 1.70 (1.2-2.5), p = 4 × 10-3). PTPRD rs324498, a previously reported RHTN signal, was among the top signals in INVEST (OR = 1.60 (1.3-2.0), p = 3.4 × 10-5) and replicated in SPS3 (OR = 1.60 (1.1-2.4), one-sided p = 0.005). Participants with the highest number of risk alleles were at increased risk of RHTN compared to participants with a lower number (p-trend = 1.8 × 10-15). Overall, we identified and replicated associations with RHTN in the MSX2, IFLTD1, and PTPRD regions, and combined these associations to create a genetic risk score.


Assuntos
Hipertensão/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Verapamil/uso terapêutico
14.
Curr Protoc Hum Genet ; 100(1): e80, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30516347

RESUMO

Electronic health records contain patient-level data collected during and for clinical care. Data within the electronic health record include diagnostic billing codes, procedure codes, vital signs, laboratory test results, clinical imaging, and physician notes. With repeated clinic visits, these data are longitudinal, providing important information on disease development, progression, and response to treatment or intervention strategies. The near universal adoption of electronic health records nationally has the potential to provide population-scale real-world clinical data accessible for biomedical research, including genetic association studies. For this research potential to be realized, high-quality research-grade variables must be extracted from these clinical data warehouses. We describe here common and emerging electronic phenotyping approaches applied to electronic health records, as well as current limitations of both the approaches and the biases associated with these clinically collected data that impact their use in research. © 2018 by John Wiley & Sons, Inc.


Assuntos
Mineração de Dados , Registros Eletrônicos de Saúde , Algoritmos , Humanos , Fenótipo
15.
BMC Med Genomics ; 11(Suppl 3): 66, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30255797

RESUMO

BACKGROUND: High levels of triglycerides (TG ≥200 mg/dL) are an emerging risk factor for cardiovascular disease. Conversely, very low levels of TG are associated with decreased risk for cardiovascular disease. Precision medicine aims to capitalize on recent findings that rare variants such as APOC3 R19X (rs76353203) are associated with risk of disease, but it is unclear how population-based associations can be best translated in clinical settings at the individual-patient level. METHODS: To explore the potential usefulness of screening for genetic predictors of cardiovascular disease, we surveyed BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records (EHRs), for APOC3 19X mutations among adult European American patients (> 45 and > 55 years of age for men and women, respectively) with the lowest percentile of TG levels. The initial search identified 262 patients with the lowest TG levels in the biorepository; among these, 184 patients with sufficient DNA and the lowest TG levels were chosen for Illumina ExomeChip genotyping. RESULTS: A total of two patients were identified as heterozygotes of APOC3 R19X for a minor allele frequency (MAF) of 0.55% in this patient population. Both heterozygous patients had only a single mention of TG in the EHR (31 and 35 mg/dL, respectively), and one patient had evidence of previous cardiovascular disease. CONCLUSIONS: In this patient population, we identified two patients who were carriers of the APOC3 19X null variant, but only one lacked evidence of disease in the EHR highlighting the challenges of inclusion of functional or previously associated genetic variation in clinical risk assessment.


Assuntos
Apolipoproteína C-III/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Registros Eletrônicos de Saúde/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Feminino , Seguimentos , Frequência do Gene , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico
16.
BMC Med Genomics ; 11(Suppl 3): 70, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30255811

RESUMO

BACKGROUND: Glaucoma is a leading cause of blindness in developed countries. Primary open-angle glaucoma (POAG), the most prevalent clinical subtype of glaucoma in the United States, affects African Americans at a higher rate compared with European Americans. Risk factors identified for POAG include increased age and family history, which coupled with heritability estimates, suggest this complex condition is associated with genetic and environmental factors. To date, several genome-wide studies have identified loci significantly associated with POAG risk, but most of these studies were performed in populations of European-descent. METHODS: To identify population-specific and trans-population genetic associations for POAG, we genotyped 11,521 African Americans using the Illumina Metabochip as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study accessing BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records. Among this study population, we identified 138 cases of POAG and 1376 controls and performed Metabochip-wide tests of association. We also estimated local genetic ancestry at CDKN2B-AS1, a POAG-associated locus established in European-descent populations. RESULTS: Overall, we did not identify significant single SNP-POAG associations after adjusting for multiple testing. We did, however, detect a significant association between POAG risk and local African genetic ancestry at CDKN2B-AS1, where on average cases were of 90% African descent compared with controls at 58% (p = 2 × 10- 6). CONCLUSIONS: These data suggest that CDKN2B-AS1 is an important locus for POAG risk among African Americans, warranting further investigation to identify the variants underlying this association.


Assuntos
Afro-Americanos/genética , Registros Eletrônicos de Saúde/estatística & dados numéricos , Predisposição Genética para Doença , Glaucoma de Ângulo Aberto/etnologia , Glaucoma de Ângulo Aberto/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Afro-Americanos/estatística & dados numéricos , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos
17.
PLoS One ; 13(7): e0200486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044860

RESUMO

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.


Assuntos
Variação Biológica da População/genética , Menarca/genética , Menopausa/genética , Fatores Etários , Alelos , Variação Biológica da População/etnologia , Feminino , Loci Gênicos/genética , Genótipo , Humanos , Menarca/etnologia , Menopausa/etnologia , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
PeerJ ; 6: e5149, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29967758

RESUMO

Effective approaches for assessing mitochondrial DNA (mtDNA) variation are important to multiple scientific disciplines. Mitochondrial haplogroups characterize branch points in the phylogeny of mtDNA. Several tools exist for mitochondrial haplogroup classification. However, most require full or partial mtDNA sequence which is often cost prohibitive for studies with large sample sizes. The purpose of this study was to develop Hi-MC, a high-throughput method for mitochondrial haplogroup classification that is cost effective and applicable to large sample sizes making mitochondrial analysis more accessible in genetic studies. Using rigorous selection criteria, we defined and validated a custom panel of mtDNA single nucleotide polymorphisms that allows for accurate classification of European, African, and Native American mitochondrial haplogroups at broad resolution with minimal genotyping and cost. We demonstrate that Hi-MC performs well in samples of European, African, and Native American ancestries, and that Hi-MC performs comparably to a commonly used classifier. Implementation as a software package in R enables users to download and run the program locally, grants greater flexibility in the number of samples that can be run, and allows for easy expansion in future revisions. Hi-MC is available in the CRAN repository and the source code is freely available at https://github.com/vserch/himc.

19.
Artigo em Inglês | MEDLINE | ID: mdl-29888042

RESUMO

Germline and somatic genomic variation represent the bulk of 'omics data available for precision medicine research. These data, however, may fail to capture the dynamic biological processes that underlie disease development, particularly for chronic diseases of aging such as chronic kidney disease (CKD). To demonstrate the value of additional dynamic precision medicine data, we sequenced somatic T-cell receptor rearrangements, markers of the adaptive immune response, from genomic DNA collected during a clinical encounter from 15 participants with CKD and associated co-morbidities. Participants were consented as part of a larger precision medicine research project at the MetroHealth System, a large urban public hospital in Cleveland, Ohio. Despite the limited sample size, we observed reduced T-cell receptor diversity in relation to biomarkers (creatinine and BUN) of CKD status in this older and mostly African American sample. Overall, these data suggest a relationship between advanced CKD and premature aging of the adaptive immune system and highlight the potential of dynamic 'omic data to generate novel hypotheses about disease mechanisms and unique opportunities for precision medicine applications.

20.
J Pers Med ; 8(3)2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29949895

RESUMO

Multiple ongoing, government-funded national efforts longitudinally collect health data and biospecimens for precision medicine research with ascertainment strategies increasingly emphasizing underrepresented groups in biomedical research. We surveyed chronic kidney disease patients from an academic, public integrated tertiary care system in Cleveland, Ohio, to examine local attitudes toward participation in large-scale government-funded studies. Responses (n = 103) indicate the majority (71%) would participate in a hypothetical national precision medicine cohort and were willing to send biospecimens to a national repository and share de-identified data, but <50% of respondents were willing to install a phone app to track personal data. The majority of participants (62%) indicated that return of research results was very important, and the majority (54%) also wanted all of their research-collected health and genetic data returned. Response patterns did not differ by race/ethnicity. Overall, we found high willingness to participate among this Cleveland patient population already participating in a local genetic study. These data suggest that despite common perceptions, subjects from communities traditionally underrepresented in genetic research will participate and agree to store samples and health data in repositories. Furthermore, most participants want return of research results, which will require a plan to provide these data in a secure, accessible, and understandable manner.

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