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1.
Commun Biol ; 4(1): 1132, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580418

RESUMO

Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.

3.
Nat Genet ; 53(8): 1135-1142, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34282336

RESUMO

Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those variants based on the effects of transmitted and nontransmitted alleles on birth weight. Out of 141 clustered variants, 22 were consistent with parent-of-origin-specific effects. We further used haplotype-specific polygenic risk scores to directly test the relationship between adult traits and birth weight. Our results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure-raising alleles reduce birth weight largely through the fetal genome.


Assuntos
Peso ao Nascer/genética , Desenvolvimento Fetal/genética , Adulto , Glicemia/genética , Pressão Sanguínea/genética , Estatura/genética , Doenças Cardiovasculares/genética , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Islândia , Recém-Nascido , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
5.
Eur Heart J ; 42(20): 1959-1971, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33580673

RESUMO

AIMS: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. METHODS AND RESULTS: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). CONCLUSION: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.


Assuntos
Fibrilação Atrial , Diabetes Mellitus Tipo 2 , Marca-Passo Artificial , Fibrilação Atrial/genética , Estudo de Associação Genômica Ampla , Humanos , Canal de Sódio Disparado por Voltagem NAV1.8 , Síndrome do Nó Sinusal/genética
7.
Circ Genom Precis Med ; 14(1): e003029, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33315477

RESUMO

BACKGROUND: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. METHODS: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. RESULTS: We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P=8.4×10-8). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (P=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (P=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. CONCLUSIONS: Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans.

8.
Nat Commun ; 11(1): 5976, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239696

RESUMO

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.


Assuntos
Predisposição Genética para Doença , Hipertensão Induzida pela Gravidez/genética , Herança Multifatorial , Pré-Eclâmpsia/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Ásia Central/epidemiologia , Pressão Sanguínea/genética , Estudos de Casos e Controles , Conjuntos de Dados como Assunto , Europa (Continente)/epidemiologia , Feminino , Fator 5 de Crescimento de Fibroblastos/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Proteína do Locus do Complexo MDS1 e EVI1/genética , Pessoa de Meia-Idade , Pré-Eclâmpsia/epidemiologia , Gravidez , Estudos Prospectivos
9.
Nat Genet ; 52(12): 1314-1332, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33230300

RESUMO

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.


Assuntos
Pressão Sanguínea/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Hipertensão/genética , Fator de Transcrição GATA5/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Mutação/genética , Fosfolipase C beta/genética , Polimorfismo de Nucleotídeo Único/genética
11.
Eur Heart J ; 41(28): 2618-2628, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32702746

RESUMO

AIMS: To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols. METHODS AND RESULTS: We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4). CONCLUSIONS: Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.


Assuntos
Doença da Artéria Coronariana , Fitosteróis , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Humanos , Islândia , Esteróis
12.
Commun Biol ; 3(1): 189, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327693

RESUMO

Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = -1.61 SD, CI95 = [-1.98, -1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.


Assuntos
Eritropoese/genética , Mutação com Ganho de Função , Hemoglobinas/metabolismo , Proteína 1 Reguladora do Ferro/genética , Mutação com Perda de Função , Biomarcadores/sangue , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Humanos , Islândia , Proteína 1 Reguladora do Ferro/metabolismo , Reino Unido
13.
Nat Commun ; 11(1): 163, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919418

RESUMO

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.


Assuntos
Fibrilação Atrial/genética , Cardiomiopatias/genética , Doença da Artéria Coronariana/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Função Ventricular Esquerda/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Cardiomiopatias/patologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Inibidor de Quinase Dependente de Ciclina p21/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Fatores de Risco
14.
JAMA Cardiol ; 5(1): 13-20, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31746962

RESUMO

Importance: Genetic studies have evaluated the influence of blood lipid levels on the risk of coronary artery disease (CAD), but less is known about how they are associated with the extent of coronary atherosclerosis. Objective: To estimate the contributions of genetically predicted blood lipid levels on the extent of coronary atherosclerosis. Design, Setting, and Participants: This genetic study included Icelandic adults who had undergone coronary angiography or assessment of coronary artery calcium using cardiac computed tomography. The study incorporates data collected from January 1987 to December 2017 in Iceland in the Swedish Coronary Angiography and Angioplasty Registry and 2 registries of individuals who had undergone percutaneous coronary interventions and coronary artery bypass grafting. For each participant, genetic scores were calculated for levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, based on reported effect sizes of 345 independent, lipid-associated variants. The genetic scores' predictive ability for lipid levels was assessed in more than 87 000 Icelandic adults. A mendelian randomization approach was used to estimate the contribution of each lipid trait. Exposures: Genetic scores for levels of non-HDL-C, LDL-C, HDL-C, and triglycerides. Main Outcomes and Measures: The extent of angiographic CAD and coronary artery calcium quantity. Results: A total of 12 460 adults (mean [SD] age, 65.1 [10.7] years; 8383 men [67.3%]) underwent coronary angiography, and 4837 had coronary artery calcium assessed by computed tomography. A genetically predicted increase in non-HDL-C levels by 1 SD (38 mg/dL [to convert to millimoles per liter, multiply by 0.0259]) was associated with greater odds of obstructive CAD (odds ratio [OR], 1.83 [95% CI, 1.63-2.07]; P = 2.8 × 10-23). Among patients with obstructive CAD, there were significant associations with multivessel disease (OR, 1.26 [95% CI, 1.11-1.44]; P = 4.1 × 10-4) and 3-vessel disease (OR, 1.47 [95% CI, 1.26-1.72]; P = 9.2 × 10-7). There were also significant associations with the presence of coronary artery calcium (OR, 2.04 [95% CI, 1.70-2.44]; P = 5.3 × 10-15) and loge-transformed coronary artery calcium (effect, 0.70 [95% CI, 0.53-0.87]; P = 1.0 × 10-15). Genetically predicted levels of non-HDL-C remained associated with obstructive CAD and coronary artery calcium extent even after accounting for the association with LDL-C. Genetically predicted levels of HDL-C and triglycerides were associated individually with the extent of coronary atherosclerosis, but not after accounting for the association with non-HDL cholesterol. Conclusions and Relevance: In this study, genetically predicted levels of non-HDL-C were associated with the extent of coronary atherosclerosis as estimated by 2 different methods. The association was stronger than for genetically predicted levels of LDL-C. These findings further support the notion that non-HDL-C may be a better marker of the overall burden of atherogenic lipoproteins than LDL-C.


Assuntos
Doença da Artéria Coronariana/fisiopatologia , Hiperlipidemias/genética , Calcificação Vascular/fisiopatologia , Idoso , Causalidade , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Angiografia Coronária , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/terapia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/epidemiologia , Islândia/epidemiologia , Modelos Logísticos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Revascularização Miocárdica , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Triglicerídeos/sangue , Calcificação Vascular/epidemiologia , Calcificação Vascular/genética
15.
J Am Coll Cardiol ; 74(24): 2982-2994, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31865966

RESUMO

BACKGROUND: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). OBJECTIVES: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. METHODS: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. RESULTS: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. CONCLUSIONS: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.


Assuntos
Doença da Artéria Coronariana/sangue , Variações do Número de Cópias de DNA , Diabetes Mellitus Tipo 2/sangue , Lipoproteína(a)/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Humanos , Islândia , Kringles , Lipoproteína(a)/genética , Análise da Randomização Mendeliana , Peso Molecular , Isoformas de Proteínas/sangue , Fatores de Risco
16.
Nat Commun ; 10(1): 4803, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641117

RESUMO

Features of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease.


Assuntos
Eletrocardiografia , Coração/fisiologia , Proteínas/genética , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/genética , Feminino , Regulação da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Coração/fisiopatologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Humanos , Islândia , Masculino , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/genética
17.
Nat Commun ; 10(1): 1777, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992453

RESUMO

Nerve conduction (NC) studies generate measures of peripheral nerve function that can reveal underlying pathology due to axonal loss, demyelination or both. We perform a genome-wide association study of sural NC amplitude and velocity in 7045 Icelanders and find a low-frequency splice-donor variant in PRPH (c.996+1G>A; MAF = 1.32%) associating with decreased NC amplitude but not velocity. PRPH encodes peripherin, an intermediate filament (IF) protein involved in cytoskeletal development and maintenance of neurons. Through RNA and protein studies, we show that the variant leads to loss-of-function (LoF), as when over-expressed in a cell line devoid of other IFs, it does not allow formation of the normal filamentous structure of peripherin, yielding instead punctate protein inclusions. Recall of carriers for neurological assessment confirms that from an early age, homozygotes have significantly lower sural NC amplitude than non-carriers and are at risk of a mild, early-onset, sensory-negative, axonal polyneuropathy.


Assuntos
Condução Nervosa/genética , Periferinas/genética , Polineuropatias/genética , Sítios de Splice de RNA/genética , Nervo Sural/fisiopatologia , Adulto , Idade de Início , Idoso , Axônios/patologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Islândia/epidemiologia , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Polineuropatias/epidemiologia , Polineuropatias/fisiopatologia , Prevalência , Splicing de RNA/fisiologia
18.
Hum Mol Genet ; 28(7): 1199-1211, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476138

RESUMO

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. Two variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context.


Assuntos
Biomarcadores/análise , Biomarcadores/urina , Variação Genética/genética , Adulto , Idoso , Alelos , Feminino , Hematúria/genética , Hematúria/urina , Humanos , Concentração de Íons de Hidrogênio , Islândia , Cetose/genética , Cetose/urina , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Proteinúria/genética , Proteinúria/urina , Transportador 2 de Glucose-Sódio/genética , Sequenciamento Completo do Genoma/métodos
19.
Nat Commun ; 9(1): 5101, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504769

RESUMO

Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased risk of gallstone disease (Pro290Ser: OR = 1.36 [1.25-1.49], P = 2.1 × 10-12, MAF = 1%; Val98Ile: OR = 1.15 [1.10-1.20], P = 1.8 × 10-10, MAF = 4%). We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease.


Assuntos
Cálculos Biliares/metabolismo , Estudo de Associação Genômica Ampla/métodos , Cálculos Biliares/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Mutação de Sentido Incorreto/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/genética , alfa 1-Antitripsina/genética
20.
Circ Genom Precis Med ; 11(8): e002151, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30354339

RESUMO

BACKGROUND: Dilated cardiomyopathy (DCM) is an important cause of heart failure. Variants in >50 genes have been reported to cause DCM, but causative variants have been found in less than half of familial cases. Variants causing DCM in Iceland have not been reported before. METHODS: We performed a genome-wide association study on DCM based on whole genome sequencing. We tested the association of 32.5 million sequence variants in 424 cases and 337 689 population controls in Iceland. RESULTS: We identified 2 DCM variants in established cardiomyopathy genes, a missense variant p.Phe145Leu in NKX2-5 carried by 1 in 7100 Icelanders ( P=7.0×10-12) and a frameshift variant p.Phe1626Serfs*40 in FLNC carried by 1 in 3600 Icelanders ( P=2.1×10-10). Both variants associate with heart failure and sudden cardiac death. Additionally, p.Phe145Leu in NKX2-5 associates with high degree atrioventricular block and atrial septal defect ( P<1.4×10-4). The penetrance of serious heart disease among carriers of the NKX2-5 variant is high and higher than that of the FLNC variant. CONCLUSIONS: Two rare variants in NKX2-5 and FLNC, carried by 1 in 2400 Icelanders, cause familial DCM in Iceland. These genes have recently been associated with DCM. Given the serious consequences of these variants, we suggest screening for them in individuals with DCM and their family members, with subsequent monitoring of carriers, offering early intervention.


Assuntos
Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/genética , Morte Súbita Cardíaca/etiologia , Filaminas/genética , Proteína Homeobox Nkx-2.5/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatia Dilatada/epidemiologia , Estudos de Casos e Controles , Morte Súbita Cardíaca/epidemiologia , Feminino , Mutação da Fase de Leitura , Estudo de Associação Genômica Ampla , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Penetrância , Adulto Jovem
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