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  • 1
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    Rate of de novo mutations and the importance of father's age to disease risk (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-08-24
    Description: 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 x 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548427/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548427/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kong, Augustine -- Frigge, Michael L -- Masson, Gisli -- Besenbacher, Soren -- Sulem, Patrick -- Magnusson, Gisli -- Gudjonsson, Sigurjon A -- Sigurdsson, Asgeir -- Jonasdottir, Aslaug -- Jonasdottir, Adalbjorg -- Wong, Wendy S W -- Sigurdsson, Gunnar -- Walters, G Bragi -- Steinberg, Stacy -- Helgason, Hannes -- Thorleifsson, Gudmar -- Gudbjartsson, Daniel F -- Helgason, Agnar -- Magnusson, Olafur Th -- Thorsteinsdottir, Unnur -- Stefansson, Kari -- MH071425/MH/NIMH NIH HHS/ -- R01 MH071425/MH/NIMH NIH HHS/ -- England -- Nature. 2012 Aug 23;488(7412):471-5. doi: 10.1038/nature11396.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland. kong@decode.is〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22914163" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Autistic Disorder/epidemiology/etiology/*genetics ; Chromosomes, Human/genetics ; Female ; *Genetic Predisposition to Disease ; Genome, Human/genetics ; Humans ; Iceland/epidemiology ; Male ; Middle Aged ; Mothers ; *Mutation Rate ; Ovum/metabolism ; *Paternal Age ; Pedigree ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; Schizophrenia/epidemiology/etiology/*genetics ; Selection, Genetic/genetics ; Sequence Analysis, DNA ; Spermatozoa/metabolism ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    A mutation in APP protects against Alzheimer's disease and age-related cognitive decline (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-18
    Description: The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-beta precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease beta-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jonsson, Thorlakur -- Atwal, Jasvinder K -- Steinberg, Stacy -- Snaedal, Jon -- Jonsson, Palmi V -- Bjornsson, Sigurbjorn -- Stefansson, Hreinn -- Sulem, Patrick -- Gudbjartsson, Daniel -- Maloney, Janice -- Hoyte, Kwame -- Gustafson, Amy -- Liu, Yichin -- Lu, Yanmei -- Bhangale, Tushar -- Graham, Robert R -- Huttenlocher, Johanna -- Bjornsdottir, Gyda -- Andreassen, Ole A -- Jonsson, Erik G -- Palotie, Aarno -- Behrens, Timothy W -- Magnusson, Olafur T -- Kong, Augustine -- Thorsteinsdottir, Unnur -- Watts, Ryan J -- Stefansson, Kari -- HL-102924/HL/NHLBI NIH HHS/ -- HL-102925/HL/NHLBI NIH HHS/ -- HL-102926/HL/NHLBI NIH HHS/ -- HL-103010/HL/NHLBI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):96-9. doi: 10.1038/nature11283.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801501" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/*genetics ; Alleles ; Alzheimer Disease/*genetics/pathology/physiopathology/prevention & control ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Protein Precursor/chemistry/*genetics/*metabolism ; Aspartic Acid Endopeptidases/metabolism ; Cognition/physiology ; Cognition Disorders/*genetics/*physiopathology/prevention & control ; Genetic Predisposition to Disease ; HEK293 Cells ; Humans ; Mutation/*genetics ; Plaque, Amyloid/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-07
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Styrkarsdottir, Unnur -- Thorleifsson, Gudmar -- Sulem, Patrick -- Gudbjartsson, Daniel F -- Sigurdsson, Asgeir -- Jonasdottir, Aslaug -- Jonasdottir, Adalbjorg -- Oddsson, Asmundur -- Helgason, Agnar -- Magnusson, Olafur T -- Walters, G Bragi -- Frigge, Michael L -- Helgadottir, Hafdis T -- Johannsdottir, Hrefna -- Bergsteinsdottir, Kristin -- Ogmundsdottir, Margret H -- Center, Jacqueline R -- Nguyen, Tuan V -- Eisman, John A -- Christiansen, Claus -- Steingrimsson, Erikur -- Jonasson, Jon G -- Tryggvadottir, Laufey -- Eyjolfsson, Gudmundur I -- Theodors, Asgeir -- Jonsson, Thorvaldur -- Ingvarsson, Thorvaldur -- Olafsson, Isleifur -- Rafnar, Thorunn -- Kong, Augustine -- Sigurdsson, Gunnar -- Masson, Gisli -- Thorsteinsdottir, Unnur -- Stefansson, Kari -- HL-102923/HL/NHLBI NIH HHS/ -- HL-102924/HL/NHLBI NIH HHS/ -- HL-102925/HL/NHLBI NIH HHS/ -- HL-102926/HL/NHLBI NIH HHS/ -- HL-103010/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 May 23;497(7450):517-20. doi: 10.1038/nature12124. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE Genetics/Amgen, 101 Reykjavik, Iceland. unnurth@decode.is〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644456" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Australia ; Biliary Tract Neoplasms/*genetics ; Bone Density/*genetics ; Carcinoma, Squamous Cell/*genetics ; Codon, Nonsense/*genetics ; Denmark ; Down-Regulation/genetics ; Female ; Heterozygote ; Humans ; Iceland ; Male ; Menarche/genetics ; Mice ; Mice, Knockout ; Osteoporotic Fractures/*genetics ; Phenotype ; Receptors, G-Protein-Coupled/chemistry/deficiency/*genetics/metabolism ; Skin Neoplasms/*genetics ; Testosterone/analysis ; Water-Electrolyte Imbalance/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Rare mutations associating with serum creatinine and chronic kidney disease (2014)
    Oxford University Press
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    Publication Date: 2014-11-27
    Description: 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.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer (2014)
    Rafnar, T., Sulem, P., Thorleifsson, G., Vermeulen, S. H., Helgason, H., Saemundsdottir, J., Gudjonsson, S. A., Sigurdsson, A., Stacey, S. N., Gudmundsson, J., Johannsdottir, H., Alexiusdottir, K., Petursdottir, V., Nikulasson, S., Geirsson, G., Jonsson, T., Aben, K. K. H., Grotenhuis, A. J., Verhaegh, G. W., Dudek, A. M., Witjes, J. A., van der Heijden, A. G., Vrieling, A., Galesloot, T. E., De Juan, A., Panadero, A., Rivera, F., Hurst, C., Bishop, D. T., Sak, S. C., Choudhury, A., Teo, M. T. W., Arici, C., Carta, A., Toninelli, E., de Verdier, P., Rudnai, P., Gurzau, E., Koppova, K., van der Keur, K. A., Lurkin, I., Goossens, M., Kellen, E., Guarrera, S., Russo, A., Critelli, R., Sacerdote, C., Vineis, P., Krucker, C., Zeegers, M. P., Gerullis, H., Ovsiannikov, D., Volkert, F., Hengstler, J. G., Selinski, S., Magnusson, O. T., Masson, G., Kong, A., Gudbjartsson, D., Lindblom, A., Zwarthoff, E., Porru, S., Golka, K., Buntinx, F., Matullo, G., Kumar, R., Mayordomo, J. I., Steineck, D. G., Kiltie, A. E., Jonsson, E., Radvanyi, F., Knowles, M. A., Thorsteinsdottir, U., Kiemeney, L. A., Stefansson, K.
    Oxford University Press
    Details
    Publication Date: 2014-09-20
    Description: Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 x 10 –11 for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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