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1.
HGG Adv ; 2(1)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-34734193

RESUMO

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

3.
Nat Genet ; 53(10): 1504-1516, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34611364

RESUMO

Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.


Assuntos
Variação Genética , Genética Populacional , Infecções por HIV/genética , Antígenos HLA/genética , Interações Hospedeiro-Patógeno/genética , Mapeamento Físico do Cromossomo , Alelos , Aminoácidos/genética , Frequência do Gene/genética , HIV-1/genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Padrões de Referência , Seleção Genética , Carga Viral
4.
Sci Rep ; 11(1): 19365, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588469

RESUMO

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

5.
Am J Hum Genet ; 108(10): 1836-1851, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34582791

RESUMO

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.


Assuntos
Asma/epidemiologia , Biomarcadores/metabolismo , Dermatite Atópica/epidemiologia , Leucócitos/patologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Locos de Características Quantitativas , Asma/genética , Asma/metabolismo , Asma/patologia , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Prognóstico , Proteoma/análise , Proteoma/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Sequenciamento Completo do Genoma
6.
PLoS One ; 16(7): e0253611, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34214102

RESUMO

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.


Assuntos
Grupos de Populações Continentais/genética , Força da Mão/fisiologia , Sequenciamento Completo do Genoma/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Grupos de Populações Continentais/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/estatística & dados numéricos
7.
Circ Genom Precis Med ; 14(4): e003258, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34241534

RESUMO

BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P=2.0×10-8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN, encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (P<3.1×10-4) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

9.
Am J Ophthalmol ; 233: 111-123, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34166655

RESUMO

To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses. METHODS: We analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Americans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in 4 pathway and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was <.05. RESULTS: Five gene sets were significantly enriched for numerous modest genetic associations with DR in one method (MAGENTA or MAGMA) and also at least nominally significant (uncorrected P < .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment, Pcorr = .014); nitric oxide biosynthesis (1.92-fold enrichment, Pcorr = .022); lipid digestion, mobilization, and transport (1.6-fold enrichment, P = .032); apoptosis (1.53-fold enrichment, P = .041); and retinal ganglion cell degeneration (2-fold enrichment, Pcorr = .049). The interferon gamma (IFNG) gene, previously implicated in DR by protein-protein interactions in our GWAS, was among the top ranked genes in the nitric oxide pathway (best variant P = .0001). CONCLUSIONS: These GSEA indicate that variants in genes involved in oxidative stress, lipid transport and catabolism, and cell degeneration are enriched for genes associated with DR risk.

10.
Bioinformatics ; 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33989384

RESUMO

SUMMARY: The sparse allele vectors (SAV) file format is an efficient storage format for large-scale DNA variation data and is designed for high throughput association analysis by leveraging techniques for fast deserialization of data into computer memory. A command line interface has been developed to complement the storage format and supports basic features like importing, exporting and subsetting. Additionally, a C ++ programming API is available allowing for easy integration into analysis software. AVAILABILITY AND IMPLEMENTATION: https://github.com/statgen/savvy. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

12.
Hum Mol Genet ; 30(15): 1443-1456, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-33856023

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.

13.
Am J Hum Genet ; 108(5): 874-893, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887194

RESUMO

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.


Assuntos
Eritrócitos/metabolismo , Eritrócitos/patologia , Estudo de Associação Genômica Ampla , National Heart, Lung, and Blood Institute (U.S.)/organização & administração , Fenótipo , Adulto , Idoso , Cromossomos Humanos Par 16/genética , Conjuntos de Dados como Assunto , Feminino , Edição de Genes , Variação Genética/genética , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Controle de Qualidade , Reprodutibilidade dos Testes , Estados Unidos
14.
Genetics ; 218(1)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33720349

RESUMO

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

16.
Nature ; 590(7845): 290-299, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568819

RESUMO

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Genômica , National Heart, Lung, and Blood Institute (U.S.) , Medicina de Precisão , Citocromo P-450 CYP2D6/genética , Haplótipos/genética , Heterozigoto , Humanos , Mutação INDEL , Mutação com Perda de Função , Mutagênese , Fenótipo , Polimorfismo de Nucleotídeo Único , Densidade Demográfica , Medicina de Precisão/normas , Controle de Qualidade , Tamanho da Amostra , Estados Unidos , Sequenciamento Completo do Genoma/normas
17.
Nat Commun ; 12(1): 24, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402679

RESUMO

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.


Assuntos
Anorexia Nervosa/genética , Glicemia/metabolismo , Intolerância à Glucose/genética , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina/genética , Insulina/sangue , Fatores de Transcrição Kruppel-Like/genética , Adulto , Anorexia Nervosa/sangue , Anorexia Nervosa/etnologia , Anorexia Nervosa/fisiopatologia , Grupo com Ancestrais do Continente Europeu , Jejum/sangue , Feminino , Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Intolerância à Glucose/sangue , Intolerância à Glucose/etnologia , Intolerância à Glucose/fisiopatologia , Humanos , Proteínas Substratos do Receptor de Insulina/sangue , Fatores de Transcrição Kruppel-Like/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Caracteres Sexuais , Fatores Sexuais , Relação Cintura-Quadril
18.
EBioMedicine ; 63: 103157, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418499

RESUMO

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.


Assuntos
Genômica , Taxa de Filtração Glomerular , Medicina de Precisão , Sequenciamento Completo do Genoma , Alelos , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Masculino , National Heart, Lung, and Blood Institute (U.S.) , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Vigilância em Saúde Pública , Característica Quantitativa Herdável , Estados Unidos/epidemiologia
19.
Mol Psychiatry ; 26(6): 2111-2125, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32372009

RESUMO

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.


Assuntos
Estudo de Associação Genômica Ampla , Hipertensão , Pressão Sanguínea/genética , Epistasia Genética , Loci Gênicos , Humanos , Hipertensão/genética , Polimorfismo de Nucleotídeo Único
20.
Nat Commun ; 11(1): 6285, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293549

RESUMO

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.


Assuntos
Doença de Alzheimer/genética , Doenças de Pequenos Vasos Cerebrais/genética , Hipertensão/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Imagem de Tensor de Difusão , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/epidemiologia , Masculino , Anamnese , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Substância Branca/diagnóstico por imagem , Adulto Jovem
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