The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Daniel F. Gudbjartsson - One of the best experts on this subject based on the ideXlab platform.
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brain age prediction using deep learning uncovers associated sequence variants
Nature Communications, 2019Co-Authors: Gyda Bjornsdottir, Daniel F. Gudbjartsson, Bragi G Walters, Benedikt Atli Jonsson, Thorgeir E Thorgeirsson, Lotta Maria Ellingsen, Hreinn StefanssonAbstract:Machine learning algorithms can be trained to estimate age from brain structural MRI. The difference between an individual's predicted and chronological age, predicted age difference (PAD), is a phenotype of relevance to aging and brain disease. Here, we present a new deep learning approach to predict brain age from a T1-weighted MRI. The method was trained on a dataset of healthy Icelanders and tested on two datasets, IXI and UK Biobank, utilizing transfer learning to improve accuracy on new sites. A genome-wide association study (GWAS) of PAD in the UK Biobank data (discovery set: [Formula: see text], replication set: [Formula: see text]) yielded two sequence variants, rs1452628-T ([Formula: see text], [Formula: see text]) and rs2435204-G ([Formula: see text], [Formula: see text]). The former is near KCNK2 and correlates with reduced sulcal width, whereas the latter correlates with reduced white matter surface area and tags a well-known inversion at 17q21.31 (H2).
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graphtyper2 enables population scale genotyping of structural variation using pangenome graphs
Nature Communications, 2019Co-Authors: Hannes P Eggertsson, Daniel F. Gudbjartsson, Hakon Jonsson, Snaedis Kristmundsdottir, Doruk Beyter, Astros Skuladottir, Marteinn T Hardarson, Kari StefanssonAbstract:Analysis of sequence diversity in the human genome is fundamental for genetic studies. Structural variants (SVs) are frequently omitted in sequence analysis studies, although each has a relatively large impact on the genome. Here, we present GraphTyper2, which uses pangenome graphs to genotype SVs and small variants using short-reads. Comparison to the syndip benchmark dataset shows that our SV genotyping is sensitive and variant segregation in families demonstrates the accuracy of our approach. We demonstrate that incorporating public assembly data into our pipeline greatly improves sensitivity, particularly for large insertions. We validate 6,812 SVs on average per genome using long-read data of 41 Icelanders. We show that GraphTyper2 can simultaneously genotype tens of thousands of whole-genomes by characterizing 60 million small variants and half a million SVs in 49,962 Icelanders, including 80 thousand SVs with high-confidence.
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relatedness disequilibrium regression estimates heritability without environmental bias
Nature Genetics, 2018Co-Authors: Alexander I. Young, Michael L. Frigge, Gyda Bjornsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gisli MassonAbstract:Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects. Relatedness disequilibrium regression is a new method for estimating heritability that removes environmental bias by taking advantage of variation in relatedness due to random Mendelian segregation.
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relatedness disequilibrium regression estimates heritability without environmental bias
Nature Genetics, 2018Co-Authors: Alexander I. Young, Michael L. Frigge, Gyda Bjornsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gisli MassonAbstract:Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects.
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a frameshift deletion in the sarcomere gene myl4 causes early onset familial atrial fibrillation
European Heart Journal, 2017Co-Authors: Hilma Holm, Jona Saemundsdottir, Hafdis T Helgadottir, Gisli Masson, Patrick Sulem, Asmundur Oddsson, Olafur T. Magnusson, Daniel F. Gudbjartsson, Hannes HelgasonAbstract:Aims Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. Methods and results We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. Conclusions Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.
Patrick Sulem - One of the best experts on this subject based on the ideXlab platform.
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relatedness disequilibrium regression estimates heritability without environmental bias
Nature Genetics, 2018Co-Authors: Alexander I. Young, Michael L. Frigge, Gyda Bjornsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gisli MassonAbstract:Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects.
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relatedness disequilibrium regression estimates heritability without environmental bias
Nature Genetics, 2018Co-Authors: Alexander I. Young, Michael L. Frigge, Gyda Bjornsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gisli MassonAbstract:Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects. Relatedness disequilibrium regression is a new method for estimating heritability that removes environmental bias by taking advantage of variation in relatedness due to random Mendelian segregation.
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A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta
European heart journal, 2018Co-Authors: Thorsteinn Bjornsson, Patrick Sulem, Anna Helgadottir, Rosa B. Thorolfsdottir, Garðar Sveinbjörnsson, Gudmundur L. Norddahl, Solveig Gretarsdottir, Audur Magnusdottir, Ragnar Danielsen, Engilbert SigurdssonAbstract: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.
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selection against variants in the genome associated with educational attainment
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Hreinn Stefansson, Alexander I. Young, Michael L. Frigge, Gudmar Thorleifsson, Florian Zink, Augustine Kong, Gudrun A Jonsdottir, Aysu Okbay, Patrick SulemAbstract:Epidemiological and genetic association studies show that genetics play an important role in the attainment of education. Here, we investigate the effect of this genetic component on the reproductive history of 109,120 Icelanders and the consequent impact on the gene pool over time. We show that an educational attainment polygenic score, POLYEDU, constructed from results of a recent study is associated with delayed reproduction (P < 10-100) and fewer children overall. The effect is stronger for women and remains highly significant after adjusting for educational attainment. Based on 129,808 Icelanders born between 1910 and 1990, we find that the average POLYEDU has been declining at a rate of ∼0.010 standard units per decade, which is substantial on an evolutionary timescale. Most importantly, because POLYEDU only captures a fraction of the overall underlying genetic component the latter could be declining at a rate that is two to three times faster.
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a frameshift deletion in the sarcomere gene myl4 causes early onset familial atrial fibrillation
European Heart Journal, 2017Co-Authors: Hilma Holm, Jona Saemundsdottir, Hafdis T Helgadottir, Gisli Masson, Patrick Sulem, Asmundur Oddsson, Olafur T. Magnusson, Daniel F. Gudbjartsson, Hannes HelgasonAbstract:Aims Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. Methods and results We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. Conclusions Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.
Gudmar Thorleifsson - One of the best experts on this subject based on the ideXlab platform.
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relatedness disequilibrium regression estimates heritability without environmental bias
Nature Genetics, 2018Co-Authors: Alexander I. Young, Michael L. Frigge, Gyda Bjornsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gisli MassonAbstract:Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects.
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relatedness disequilibrium regression estimates heritability without environmental bias
Nature Genetics, 2018Co-Authors: Alexander I. Young, Michael L. Frigge, Gyda Bjornsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gisli MassonAbstract:Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects. Relatedness disequilibrium regression is a new method for estimating heritability that removes environmental bias by taking advantage of variation in relatedness due to random Mendelian segregation.
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selection against variants in the genome associated with educational attainment
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Hreinn Stefansson, Alexander I. Young, Michael L. Frigge, Gudmar Thorleifsson, Florian Zink, Augustine Kong, Gudrun A Jonsdottir, Aysu Okbay, Patrick SulemAbstract:Epidemiological and genetic association studies show that genetics play an important role in the attainment of education. Here, we investigate the effect of this genetic component on the reproductive history of 109,120 Icelanders and the consequent impact on the gene pool over time. We show that an educational attainment polygenic score, POLYEDU, constructed from results of a recent study is associated with delayed reproduction (P < 10-100) and fewer children overall. The effect is stronger for women and remains highly significant after adjusting for educational attainment. Based on 129,808 Icelanders born between 1910 and 1990, we find that the average POLYEDU has been declining at a rate of ∼0.010 standard units per decade, which is substantial on an evolutionary timescale. Most importantly, because POLYEDU only captures a fraction of the overall underlying genetic component the latter could be declining at a rate that is two to three times faster.
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epigenetic and genetic components of height regulation
Nature Communications, 2016Co-Authors: Stefania Benonisdottir, Asmundur Oddsson, Gudmar Thorleifsson, Agnar Helgason, Ragnar P Kristjansson, Gardar Sveinbjornsson, Arna Oskarsdottir, Olafur B Davidsson, Gudny A ArnadottirAbstract:Adult height is a highly heritable trait. Here we identified 31.6 million sequence variants by whole-genome sequencing of 8,453 Icelanders and tested them for association with adult height by imputing them into 88,835 Icelanders. Here we discovered 13 novel height associations by testing four different models including parent-of-origin (|β|=0.4–10.6 cm). The minor alleles of three parent-of-origin signals associate with less height only when inherited from the father and are located within imprinted regions (IGF2-H19 and DLK1-MEG3). We also examined the association of these sequence variants in a set of 12,645 Icelanders with birth length measurements. Two of the novel variants, (IGF2-H19 and TET1), show significant association with both adult height and birth length, indicating a role in early growth regulation. Among the parent-of-origin signals, we observed opposing parental effects raising questions about underlying mechanisms. These findings demonstrate that common variations affect human growth by parental imprinting. Adult height has a strong genetic component and is highly heritable. Here the authors whole-genome sequence 8,453 Icelanders and find novel parent-of-origin derived associations in IGF2-H19 and DLK1-MEG3.
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variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease
Nature Genetics, 2016Co-Authors: Anna Helgadottir, Gudmar Thorleifsson, Solveig Gretarsdottir, Audur Magnusdottir, Eirikur Hjartarson, Asgeir Sigurdsson, Aslaug Jonasdottir, Helgi Kristjansson, Patrick SulemAbstract:Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
Gisli Masson - One of the best experts on this subject based on the ideXlab platform.
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relatedness disequilibrium regression estimates heritability without environmental bias
Nature Genetics, 2018Co-Authors: Alexander I. Young, Michael L. Frigge, Gyda Bjornsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gisli MassonAbstract:Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects. Relatedness disequilibrium regression is a new method for estimating heritability that removes environmental bias by taking advantage of variation in relatedness due to random Mendelian segregation.
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relatedness disequilibrium regression estimates heritability without environmental bias
Nature Genetics, 2018Co-Authors: Alexander I. Young, Michael L. Frigge, Gyda Bjornsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Gisli MassonAbstract:Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects.
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a frameshift deletion in the sarcomere gene myl4 causes early onset familial atrial fibrillation
European Heart Journal, 2017Co-Authors: Hilma Holm, Jona Saemundsdottir, Hafdis T Helgadottir, Gisli Masson, Patrick Sulem, Asmundur Oddsson, Olafur T. Magnusson, Daniel F. Gudbjartsson, Hannes HelgasonAbstract:Aims Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. Methods and results We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. Conclusions Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.
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a germline variant in the tp53 polyadenylation signal confers cancer susceptibility
Nature Genetics, 2011Co-Authors: Simon N Stacey, Gisli Masson, Patrick Sulem, Olafur T. Magnusson, Daniel F. Gudbjartsson, Aslaug Jonasdottir, Sigurjon A Gudjonsson, Julius Gudmundsson, B Sigurgeirsson, Kristin ThorisdottirAbstract:To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We im ...
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A rare variant in MYH6 is associated with high risk of sick sinus syndrome
Nature genetics, 2011Co-Authors: Hilma Holm, Jona Saemundsdottir, Hafdis T Helgadottir, Gisli Masson, Patrick Sulem, Olafur T. Magnusson, Daniel F. Gudbjartsson, Carlo Zanon, Agnar Helgason, Arnaldur GylfasonAbstract:Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10⁻²⁹. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.
Hannes Helgason - One of the best experts on this subject based on the ideXlab platform.
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a rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease
Human Molecular Genetics, 2017Co-Authors: Eythor Bjornsson, Hannes Helgason, Anna Helgadottir, Aslaug Jonasdottir, Arnaldur Gylfason, Birte Kehr, Gisli H Halldorsson, Asgeir SigurdssonAbstract: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 (β = 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.
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diversity in non repetitive human sequences not found in the reference genome
Nature Genetics, 2017Co-Authors: Birte Kehr, Hannes Helgason, Anna Helgadottir, Aslaug Jonasdottir, Pall Melsted, Hakon Jonsson, Asgeir SigurdssonAbstract:Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR) sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are ancestral. Furthermore, 149 variant loci are in linkage disequilibrium (r2 > 0.8) with a genome-wide association study (GWAS) catalog marker, suggesting disease relevance. Additionally, we report an association (P = 3.8 × 10-8, odds ratio (OR) = 0.92) with myocardial infarction (23,360 cases, 300,771 controls) for a 766-bp NRNR sequence variant. Our results underline the importance of including variation of all complexity levels when searching for variants that associate with disease.
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a frameshift deletion in the sarcomere gene myl4 causes early onset familial atrial fibrillation
European Heart Journal, 2017Co-Authors: Hilma Holm, Jona Saemundsdottir, Hafdis T Helgadottir, Gisli Masson, Patrick Sulem, Asmundur Oddsson, Olafur T. Magnusson, Daniel F. Gudbjartsson, Hannes HelgasonAbstract:Aims Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. Methods and results We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. Conclusions Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia.
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common and rare variants associating with serum levels of creatine kinase and lactate dehydrogenase
Nature Communications, 2016Co-Authors: Ragnar P Kristjansson, Hannes Helgason, Asmundur Oddsson, Aslaug Jonasdottir, Gardar Sveinbjornsson, Gudny A Arnadottir, Brynjar O Jensson, Bragi G WaltersAbstract:Creatine kinase (CK) and lactate dehydrogenase (LDH) are widely used markers of tissue damage. To search for sequence variants influencing serum levels of CK and LDH, 28.3 million sequence variants identified through whole-genome sequencing of 2,636 Icelanders were imputed into 63,159 and 98,585 people with CK and LDH measurements, respectively. Here we describe 13 variants associating with serum CK and 16 with LDH levels, including four that associate with both. Among those, 15 are non-synonymous variants and 12 have a minor allele frequency below 5%. We report sequence variants in genes encoding the enzymes being measured (CKM and LDHA), as well as in genes linked to muscular (ANO5) and immune/inflammatory function (CD163/CD163L1, CSF1, CFH, HLA-DQB1, LILRB5, NINJ1 and STAB1). A number of the genes are linked to the mononuclear/phagocyte system and clearance of enzymes from the serum. This highlights the variety in the sources of normal diversity in serum levels of enzymes.
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large scale whole genome sequencing of the icelandic population
Nature Genetics, 2015Co-Authors: Daniel F. Gudbjartsson, Hannes Helgason, Arnaldur Gylfason, Sigurjon A Gudjonsson, Florian Zink, Asmundur Oddson, Soren Besenbacher, Gisli Magnusson, Bjarni V Halldorsson, Eirikur HjartarsonAbstract:Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.
