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1.
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
2.
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
3.
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
4.
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
5.
Commun Biol ; 1: 68, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271950

RESUMO

Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.

6.
Nat Genet ; 50(9): 1234-1239, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30061737

RESUMO

To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5)1, or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an 'atrial cardiomyopathy'2, either during fetal heart development or as a response to stress in the adult heart.


Assuntos
Fibrilação Atrial/genética , Mutação/genética , Bancos de Espécimes Biológicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Cardiopatias Congênitas/genética , Humanos , Risco
7.
Nat Commun ; 9(1): 987, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29511194

RESUMO

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10-10) and aortic root diameter (P = 1.30 × 10-8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10-3) and coronary artery disease (OR = 1.05, P = 9.3 × 10-5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.


Assuntos
Estenose da Valva Aórtica/genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Fatores de Risco
8.
Eur Heart J ; 39(34): 3243-3249, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-29590334

RESUMO

Aims: Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and confers substantial morbidity despite treatment. It is increasingly recognized as a highly heritable condition. The aim of the study was to search for sequence variants that affect the risk of CoA. Methods and results: We performed a genome-wide association study of CoA among Icelanders (120 cases and 355 166 controls) based on imputed variants identified through whole-genome sequencing. We found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp in MYH6 (odds ratio = 44.2, P = 5.0 × 10-22), encoding the alpha-heavy chain subunit of cardiac myosin, an essential sarcomere protein. Approximately 20% of individuals with CoA in Iceland carry this mutation. We show that p.Arg721Trp also associates with other CHDs, in particular bicuspid aortic valve. We have previously reported broad effects of p.Arg721Trp on cardiac electrical function and strong association with sick sinus syndrome and atrial fibrillation. Conclusion: Through a population approach, we found that a rare missense mutation p.Arg721Trp in the sarcomere gene MYH6 has a strong effect on the risk of CoA and explains a substantial fraction of the Icelanders with CoA. This is the first mutation associated with non-familial or sporadic form of CoA at a population level. The p.Arg721Trp in MYH6 causes a cardiac syndrome with highly variable expressivity and emphasizes the importance of sarcomere integrity for cardiac development and function.


Assuntos
Coartação Aórtica/genética , Miosinas Cardíacas/genética , DNA/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação de Sentido Incorreto , Cadeias Pesadas de Miosina/genética , Adolescente , Adulto , Coartação Aórtica/metabolismo , Doenças Assintomáticas , Miosinas Cardíacas/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Cadeias Pesadas de Miosina/metabolismo , Linhagem , Estudos Retrospectivos , Adulto Jovem
9.
J Am Coll Cardiol ; 70(17): 2157-2168, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-29050564

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4. OBJECTIVES: The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements. METHODS: The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals. RESULTS: The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10-18), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10-10), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive. CONCLUSIONS: The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF.


Assuntos
Fibrilação Atrial/genética , Variação Estrutural do Genoma , Fibrilação Atrial/fisiopatologia , Eletrocardiografia , Estudo de Associação Genômica Ampla , Humanos , Mutação de Sentido Incorreto/genética , Cadeias Leves de Miosina/genética , Plectina/genética , Risco , Sarcômeros
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