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1.
Hum Mutat ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31692161

RESUMO

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating 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 ~50% diagnostic rate marks a relative ceiling for current WES-based methods and more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases. This article is protected by copyright. All rights reserved.

3.
Diabetes Care ; 42(9): 1784-1791, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31213470

RESUMO

OBJECTIVE: We aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/Latinos with diverse genetic ancestries. RESEARCH DESIGN AND METHODS: We conducted a genome-wide association study (GWAS) of HbA1c 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 HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (ß = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c 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 HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28). CONCLUSIONS: This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.

4.
PLoS One ; 14(6): e0217796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31251759

RESUMO

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.

5.
PLoS Genet ; 15(4): e1007739, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30990817

RESUMO

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.


Assuntos
Hexoquinase/genética , Subunidade alfa de Receptor de Interleucina-18/genética , Oxiemoglobinas/metabolismo , Sono/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Moléculas de Adesão Celular Neuronais/genética , Biologia Computacional , Proteínas da Matriz Extracelular/genética , Feminino , Redes Reguladoras de Genes , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Hipóxia/sangue , Hipóxia/genética , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas do Tecido Nervoso/genética , Oxigênio/sangue , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Serina Endopeptidases/genética , Síndromes da Apneia do Sono/sangue , Síndromes da Apneia do Sono/genética , Adulto Jovem
7.
Hum Mol Genet ; 28(7): 1212-1224, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30624610

RESUMO

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.


Assuntos
Previsões/métodos , Metaboloma/genética , Metaboloma/fisiologia , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Mapeamento Cromossômico/métodos , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética
8.
Hum Mol Genet ; 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30403821

RESUMO

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 oxyhemoglobin saturation 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.

9.
BMC Obes ; 5: 26, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30305909

RESUMO

Background: Genome-wide association studies have implicated the transcription factor 7-like 2 (TCF7L2) 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 TCF7L2. 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 TCF7L2 (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 TCF7L2 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 TCF7L2 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 TCF7L2 on obesity and type 2 diabetes across the life course.

10.
Nat Genet ; 50(11): 1505-1513, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30297969

RESUMO

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).

11.
Mol Psychiatry ; 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108311

RESUMO

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 × 10-7), an immunoglobulin gene whose antibodies interact with ß-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10-7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10-6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

12.
Hum Genet ; 137(9): 689-703, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30046887

RESUMO

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.


Assuntos
Anodontia/genética , Moléculas de Adesão Celular/genética , Marcadores Genéticos , Mutação , Proteínas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Proteínas Wnt/genética , Anodontia/epidemiologia , Anodontia/patologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Turquia/epidemiologia
14.
15.
Genetics ; 209(2): 607-616, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29610217

RESUMO

Small molecule lipid-related metabolites are important components of fatty acid and steroid metabolism-two important contributors to human health. This study investigated the extent to which rare and common genetic variants spanning the human genome influence the lipid-related metabolome. Sequence data from 1552 European-Americans (EA) and 1872 African-Americans (AA) were analyzed to examine the impact of common and rare variants on the levels of 102 circulating lipid-related metabolites measured by a combination of chromatography and mass spectroscopy. We conducted single variant tests [minor allele frequency (MAF) > 5%, statistical significance P-value ≤ 2.45 × 10-10] and tests aggregating rare variants (MAF ≤ 5%) across multiple genomic motifs, such as coding regions and regulatory domains, and sliding windows. Multiethnic meta-analyses detected 53 lipid-related metabolites-locus pairs, which were inspected for evidence of consistent signal between the two ethnic groups. Thirty-eight lipid-related metabolite-genomic region associations were consistent across ethnicities, among which seven were novel. The regions contain genes that are related to metabolite transport (SLC10A1) and metabolism (SCD, FDX1, UGT2B15, and FADS2). Six of the seven novel findings lie in expression quantitative trait loci affecting the expression levels of 14 surrounding genes in multiple tissues. Imputed expression levels of 10 of the affected genes were associated with four corresponding lipid-related traits in at least one tissue. Our findings offer valuable insight into circulating lipid-related metabolite regulation in a multiethnic population.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Metabolismo dos Lipídeos/genética , Metaboloma , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas
16.
Dement Geriatr Cogn Disord ; 45(1-2): 1-17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29486463

RESUMO

BACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.


Assuntos
Doença de Alzheimer/genética , Demência/genética , Proteínas do Tecido Nervoso/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Demência/epidemiologia , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Prevalência , Análise de Sequência de DNA
18.
Am J Respir Cell Mol Biol ; 58(3): 391-401, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29077507

RESUMO

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.


Assuntos
Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Apneia Obstrutiva do Sono/genética , Sono REM/fisiologia , Fatores de Transcrição/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidiletanolamina N-Metiltransferase/genética , Caracteres Sexuais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteínas ras/genética
19.
Sci Rep ; 7(1): 17075, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-29213071

RESUMO

QT interval prolongation is a heritable risk factor for ventricular arrhythmias and can predispose to sudden death. Most genome-wide association studies (GWAS) of QT were performed in European ancestral populations, leaving other groups uncharacterized. Herein we present the first QT GWAS of Hispanic/Latinos using data on 15,997 participants from four studies. Study-specific summary results of the association between 1000 Genomes Project (1000G) imputed SNPs and electrocardiographically measured QT were combined using fixed-effects meta-analysis. We identified 41 genome-wide significant SNPs that mapped to 13 previously identified QT loci. Conditional analyses distinguished six secondary signals at NOS1AP (n = 2), ATP1B1 (n = 2), SCN5A (n = 1), and KCNQ1 (n = 1). Comparison of linkage disequilibrium patterns between the 13 lead SNPs and six secondary signals with previously reported index SNPs in 1000G super populations suggested that the SCN5A and KCNE1 lead SNPs were potentially novel and population-specific. Finally, of the 42 suggestively associated loci, AJAP1 was suggestively associated with QT in a prior East Asian GWAS; in contrast BVES and CAP2 murine knockouts caused cardiac conduction defects. Our results indicate that whereas the same loci influence QT across populations, population-specific variation exists, motivating future trans-ethnic and ancestrally diverse QT GWAS.

20.
Sci Data ; 4: 170179, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29257133

RESUMO

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Variação Genética , Grupo com Ancestrais do Continente Europeu , Humanos
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