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1.
N Engl J Med ; 389(19): 1741-1752, 2023 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-37937776

RESUMO

BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).


Assuntos
Doença , Genômica , Longevidade , Humanos , Alelos , Testes Genéticos , Variação Genética , Genótipo , Islândia/epidemiologia , Longevidade/genética , Doença/genética , Doenças Cardiovasculares/genética , Neoplasias/genética
2.
Nature ; 549(7673): 519-522, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28959963

RESUMO

The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics and to evolutionary studies. To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35× genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32-0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45-1.57). The number of clustered mutations increases faster with the mother's age than with the father's, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19-0.33%) decrease in cytosine-phosphate-guanine to thymine-phosphate-guanine (CpG>TpG) de novo mutations and a 0.33% (95% CI 0.28-0.38%) increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C>G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.


Assuntos
Envelhecimento/genética , Mutação em Linhagem Germinativa/genética , Idade Materna , Mutagênese , Pais , Idade Paterna , Adolescente , Adulto , Idoso , Animais , Criança , Cromossomos Humanos Par 8/genética , Evolução Molecular , Feminino , Sequência Rica em GC , Genoma Humano/genética , Gorilla gorilla/genética , Humanos , Mutação INDEL , Islândia , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Pan troglodytes/genética , Polimorfismo de Nucleotídeo Único , Pongo/genética , Adulto Jovem
3.
Arterioscler Thromb Vasc Biol ; 41(10): 2616-2628, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34407635

RESUMO

Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.


Assuntos
Apolipoproteína B-100/genética , Doenças Cardiovasculares/genética , Hiperlipoproteinemia Tipo II/genética , Lipídeos/sangue , Mutação , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/terapia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/etnologia , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco , Adulto Jovem
4.
PLoS Genet ; 13(3): e1006659, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28273074

RESUMO

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (ß = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.


Assuntos
Asma/genética , Eosinófilos/metabolismo , Interleucina-33/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo , Animais , Sítios de Ligação , Bioensaio , Criança , Pré-Escolar , Dinamarca , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Islândia , Lactente , Recém-Nascido , Íntrons , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Países Baixos , Adulto Jovem
5.
Hum Mol Genet ; 26(12): 2364-2376, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28398513

RESUMO

Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (ß = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.


Assuntos
Doença da Artéria Coronariana/genética , Haptoglobinas/genética , Adulto , Alelos , Sequência de Bases , Doença da Artéria Coronariana/metabolismo , Variações do Número de Cópias de DNA/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Variação Genética , Haptoglobinas/metabolismo , Humanos , Islândia , Lipídeos/sangue , Lipídeos/genética , Lipoproteínas/genética , Masculino , Mutação , Razão de Chances , Sítios de Splice de RNA/genética , Fatores de Risco
6.
Nature ; 497(7450): 517-20, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23644456

RESUMO

Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.


Assuntos
Neoplasias do Sistema Biliar/genética , Densidade Óssea/genética , Carcinoma de Células Escamosas/genética , Códon sem Sentido/genética , Fraturas por Osteoporose/genética , Receptores Acoplados a Proteínas G/genética , Neoplasias Cutâneas/genética , Desequilíbrio Hidroeletrolítico/genética , Animais , Austrália , Dinamarca , Regulação para Baixo/genética , Feminino , Heterozigoto , Humanos , Islândia , Masculino , Menarca/genética , Camundongos , Camundongos Knockout , Fenótipo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/metabolismo , Testosterona/análise
7.
PLoS Genet ; 12(11): e1006315, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27846220

RESUMO

Mutation of the DNA molecule is one of the most fundamental processes in biology. In this study, we use 283 parent-offspring trios to estimate the rate of mutation for both single nucleotide variants (SNVs) and short length variants (indels) in humans and examine the mutation process. We found 17812 SNVs, corresponding to a mutation rate of 1.29 × 10-8 per position per generation (PPPG) and 1282 indels corresponding to a rate of 9.29 × 10-10 PPPG. We estimate that around 3% of human de novo SNVs are part of a multi-nucleotide mutation (MNM), with 558 (3.1%) of mutations positioned less than 20kb from another mutation in the same individual (median distance of 525bp). The rate of de novo mutations is greater in late replicating regions (p = 8.29 × 10-19) and nearer recombination events (p = 0.0038) than elsewhere in the genome.


Assuntos
Genoma Humano , Mutação INDEL/genética , Taxa de Mutação , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único/genética , Recombinação Genética/genética
8.
Nature ; 488(7412): 471-5, 2012 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-22914163

RESUMO

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.


Assuntos
Transtorno Autístico/genética , Predisposição Genética para Doença , Taxa de Mutação , Idade Paterna , Esquizofrenia/genética , Adulto , Transtorno Autístico/epidemiologia , Transtorno Autístico/etiologia , Cromossomos Humanos/genética , Feminino , Genoma Humano/genética , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Mães , Óvulo/metabolismo , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Esquizofrenia/epidemiologia , Esquizofrenia/etiologia , Seleção Genética/genética , Análise de Sequência de DNA , Espermatozoides/metabolismo , Adulto Jovem
9.
BMC Med Genet ; 18(1): 129, 2017 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-29137621

RESUMO

BACKGROUND: Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance. CASE PRESENTATION: Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein. CONCLUSIONS: This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome.


Assuntos
Proteína Coatomer/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Mutação de Sentido Incorreto , Artrite/diagnóstico , Artrite/genética , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Islândia , Lactente , Pneumopatias/diagnóstico , Pneumopatias/genética , Masculino , Linhagem
10.
BMC Med Genet ; 18(1): 103, 2017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28965491

RESUMO

BACKGROUND: Epileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease. CASE PRESENTATION: We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease. CONCLUSIONS: We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.


Assuntos
Epilepsia/genética , Mutação de Sentido Incorreto , Espasmos Infantis/genética , Enzimas Ativadoras de Ubiquitina/genética , Adolescente , Adulto , Idade de Início , Substituição de Aminoácidos , Criança , Pré-Escolar , Epilepsia/complicações , Feminino , Heterozigoto , Humanos , Lactente , Linhagem , Irmãos , Espasmos Infantis/complicações
11.
Hum Mol Genet ; 23(25): 6935-43, 2014 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-25082825

RESUMO

Chronic kidney disease (CKD) is a complex disorder with a strong genetic component. A number of common sequence variants have been found to associate with serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and/or CKD. We imputed 24 million single-nucleotide polymorphisms and insertions/deletions identified by whole-genome sequencing of 2230 Icelanders into 81 656 chip-typed individuals and 112 630 relatives of genotyped individuals over the age of 18 with SCr measurements. The large set of sequenced individuals allowed accurate imputation of variants to a minor allele frequency (MAF) of 0.1%. We tested the imputed variants for association with SCr. In addition to replicating established loci, we discovered missense and loss-of-function variants associating with SCr in three solute carriers (SLC6A19, SLC25A45 and SLC47A1) and two E3 ubiquitin ligases (RNF186 and RNF128). All the variants are within coding sequences and all but one are rare (MAF <2%) with SCr effects between 0.085 and 0.129 standard deviations. These rare variants have a larger effect on SCr than previously reported common variants, explaining 0.5% of the variability of SCr in Icelanders in addition to the 1% already accounted for. We tested the five variants associating with SCr for association with CKD in an Icelandic sample of 15 594 cases and 291 428 controls. Three of the variants also associated with CKD. These variants may either affect kidney function or creatinine synthesis and excretion. Of note were four mutations in SLC6A19 that associate with reduced SCr, three of which have been shown to cause Hartnup disease.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Creatinina/sangue , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Insuficiência Renal Crônica/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Taxa de Filtração Glomerular , Humanos , Mutação INDEL , Islândia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia
12.
Nature ; 467(7319): 1099-103, 2010 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-20981099

RESUMO

Meiotic recombinations contribute to genetic diversity by yielding new combinations of alleles. Recently, high-resolution recombination maps were inferred from high-density single-nucleotide polymorphism (SNP) data using linkage disequilibrium (LD) patterns that capture historical recombination events. The use of these maps has been demonstrated by the identification of recombination hotspots and associated motifs, and the discovery that the PRDM9 gene affects the proportion of recombinations occurring at hotspots. However, these maps provide no information about individual or sex differences. Moreover, locus-specific demographic factors like natural selection can bias LD-based estimates of recombination rate. Existing genetic maps based on family data avoid these shortcomings, but their resolution is limited by relatively few meioses and a low density of markers. Here we used genome-wide SNP data from 15,257 parent-offspring pairs to construct the first recombination maps based on directly observed recombinations with a resolution that is effective down to 10 kilobases (kb). Comparing male and female maps reveals that about 15% of hotspots in one sex are specific to that sex. Although male recombinations result in more shuffling of exons within genes, female recombinations generate more new combinations of nearby genes. We discover novel associations between recombination characteristics of individuals and variants in the PRDM9 gene and we identify new recombination hotspots. Comparisons of our maps with two LD-based maps inferred from data of HapMap populations of Utah residents with ancestry from northern and western Europe (CEU) and Yoruba in Ibadan, Nigeria (YRI) reveal population differences previously masked by noise and map differences at regions previously described as targets of natural selection.


Assuntos
Cromossomos Humanos/genética , Recombinação Genética/genética , Caracteres Sexuais , Alelos , Proteínas de Ligação a DNA/genética , Europa (Continente)/etnologia , Éxons/genética , Feminino , Genética Populacional , Haplótipos/genética , Heterozigoto , Histona-Lisina N-Metiltransferase/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Meiose/genética , Nigéria/etnologia , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Tamanho da Amostra , Seleção Genética/genética , Utah
13.
Nature ; 462(7275): 868-74, 2009 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-20016592

RESUMO

Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.


Assuntos
Pai , Predisposição Genética para Doença/genética , Mães , Polimorfismo de Nucleotídeo Único/genética , Alelos , Sítios de Ligação , Neoplasias da Mama/genética , Fator de Ligação a CCCTC , Carcinoma Basocelular/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 7/genética , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Genoma Humano/genética , Impressão Genômica/genética , Haplótipos , Humanos , Islândia , Masculino , Linhagem , Proteínas Repressoras/metabolismo
14.
Nature ; 452(7186): 423-8, 2008 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-18344981

RESUMO

Common human diseases result from the interplay of many genes and environmental factors. Therefore, a more integrative biology approach is needed to unravel the complexity and causes of such diseases. To elucidate the complexity of common human diseases such as obesity, we have analysed the expression of 23,720 transcripts in large population-based blood and adipose tissue cohorts comprehensively assessed for various phenotypes, including traits related to clinical obesity. In contrast to the blood expression profiles, we observed a marked correlation between gene expression in adipose tissue and obesity-related traits. Genome-wide linkage and association mapping revealed a highly significant genetic component to gene expression traits, including a strong genetic effect of proximal (cis) signals, with 50% of the cis signals overlapping between the two tissues profiled. Here we demonstrate an extensive transcriptional network constructed from the human adipose data that exhibits significant overlap with similar network modules constructed from mouse adipose data. A core network module in humans and mice was identified that is enriched for genes involved in the inflammatory and immune response and has been found to be causally associated to obesity-related traits.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Obesidade/genética , Tecido Adiposo/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sangue/metabolismo , Índice de Massa Corporal , Estudos de Coortes , Feminino , Genoma Humano , Humanos , Islândia , Escore Lod , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Tamanho da Amostra , Relação Cintura-Quadril , População Branca/genética
15.
Nature ; 455(7210): 232-6, 2008 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-18668039

RESUMO

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.


Assuntos
Predisposição Genética para Doença/genética , Esquizofrenia/genética , Deleção de Sequência/genética , China , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 15/genética , Europa (Continente) , Dosagem de Genes/genética , Genoma Humano/genética , Genótipo , Humanos , Perda de Heterozigosidade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/genética
16.
Eur J Hum Genet ; 32(1): 44-51, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37684520

RESUMO

Marfan syndrome (MFS) is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by variants in the FBN1 gene. To explore causes of MFS and the prevalence of the disease in Iceland we collected information from all living individuals with a clinical diagnosis of MFS in Iceland (n = 32) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis (27/32). Moreover, to assess a potential underdiagnosis of MFS in Iceland we attempted a genotype-based approach to identify individuals with MFS. We interrogated deCODE genetics' database of 35,712 whole-genome sequenced individuals to search for rare sequence variants in FBN1. Overall, we identified 15 pathogenic or likely pathogenic variants in FBN1 in 44 individuals, only 22 of whom were previously diagnosed with MFS. The most common of these variants, NM_000138.4:c.8038 C > T p.(Arg2680Cys), is present in a multi-generational pedigree, and was found to stem from a single forefather born around 1840. The p.(Arg2680Cys) variant associates with a form of MFS that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.(Arg2680Cys)-associated MFS. Based on these combined genetic and clinical data, we show that MFS prevalence in Iceland could be as high as 1/6,600 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder.


Assuntos
Síndrome de Marfan , Humanos , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/epidemiologia , Síndrome de Marfan/genética , Islândia/epidemiologia , Fibrilina-1/genética , Genótipo , Linhagem , Mutação , Adipocinas/genética
17.
Hum Mol Genet ; 20(10): 2071-7, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21357676

RESUMO

Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), The Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10(-14)) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10(-11)). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers.


Assuntos
Café/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Comportamento de Ingestão de Líquido/fisiologia , Variação Genética , Receptores de Hidrocarboneto Arílico/genética , Adulto , Idoso , Alelos , Cromossomos Humanos Par 15 , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Fatores Sexuais
18.
Nature ; 448(7151): 353-7, 2007 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-17603472

RESUMO

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart.


Assuntos
Fibrilação Atrial/genética , Cromossomos Humanos Par 4/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Fibrilação Atrial/diagnóstico , Feminino , Frequência do Gene , Genoma Humano/genética , Haplótipos/genética , Hong Kong , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Suécia , Estados Unidos , População Branca/genética
19.
Nat Genet ; 55(11): 1843-1853, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37884687

RESUMO

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.


Assuntos
Epilepsia , Transtornos de Enxaqueca , Enxaqueca com Aura , Humanos , Estudo de Associação Genômica Ampla , Transtornos de Enxaqueca/genética , Enxaqueca com Aura/genética , Fenótipo
20.
Commun Biol ; 5(1): 525, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35650273

RESUMO

The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huët anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huët anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huët anomaly in an Icelandic eight generation pedigree, initially reported in 1963. Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology.


Assuntos
Anomalia de Pelger-Huët , Estudo de Associação Genômica Ampla , Granulócitos/metabolismo , Humanos , Islândia , Neutrófilos/metabolismo , Anomalia de Pelger-Huët/genética
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