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3 results on '"Lopez de Lapuente Portilla, Aitzkoa"'

1. Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Author

Oddsson, Asmundur, Sulem, Patrick, Sveinbjornsson, Gardar, Arnadottir, Gudny A, Steinthorsdottir, Valgerdur, Halldorsson, Gisli H, Atlason, Bjarni A, Oskarsson, Gudjon R, Helgason, Hannes, Nielsen, Henriette Svarre, Westergaard, David, Karjalainen, Juha M, Katrinardottir, Hildigunnur, Fridriksdottir, Run, Jensson, Brynjar O, Tragante, Vinicius, Ferkingstad, Egil, Jonsson, Hakon, Gudjonsson, Sigurjon A, Beyter, Doruk, Moore, Kristjan H S, Thordardottir, Helga B, Kristmundsdottir, Snaedis, Stefansson, Olafur A, Rantapää-Dahlqvist, Solbritt, Sonderby, Ida Elken, Didriksen, Maria, Stridh, Pernilla, Haavik, Jan, Tryggvadottir, Laufey, Frei, Oleksandr, Walters, G Bragi, Kockum, Ingrid, Hjalgrim, Henrik, Olafsdottir, Thorunn A, Selbaek, Geir, Nyegaard, Mette, Erikstrup, Christian, Brodersen, Thorsten, Saevarsdottir, Saedis, Olsson, Tomas, Nielsen, Kaspar Rene, Haraldsson, Asgeir, Bruun, Mie Topholm, Hansen, Thomas Folkmann, Steingrimsdottir, Thora, Jacobsen, Rikke Louise, Lie, Rolv T, Djurovic, Srdjan, Alfredsson, Lars, Lopez de Lapuente Portilla, Aitzkoa, Brunak, Soren, Melsted, Pall, Halldorsson, Bjarni V, Saemundsdottir, Jona, Magnusson, Olafur Th, Padyukov, Leonid, Banasik, Karina, Rafnar, Thorunn, Askling, Johan, Klareskog, Lars, Pedersen, Ole Birger, Masson, Gisli, Havdahl, Alexandra, Nilsson, Bjorn, Andreassen, Ole A, Daly, Mark, Ostrowski, Sisse Rye, Jonsdottir, Ingileif, Stefansson, Hreinn, Holm, Hilma, Helgason, Agnar, Thorsteinsdottir, Unnur, Stefansson, Kari, and Gudbjartsson, Daniel F

Subjects
Mice, Genotype, Homozygote, Proteins/genetics, Animals, Humans, Genes, Recessive
Abstract

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Published
2023
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2. Genetic regulation of fetal hemoglobin across global populations

Author

Cato, Liam D, Li, Rick, Lu, Henry Y, Yu, Fulong, Wissman, Mariel, Mkumbe, Baraka S, Ekwattanakit, Supachai, Deelen, Patrick, Mwita, Liberata, Sangeda, Raphael Zozimus, Suksangpleng, Thidarat, Riolueang, Suchada, Bronson, Paola G, Paul, Dirk S, Kawabata, Emily, Astle, William J, Aguet, Francois, Ardlie, Kristin, Lopez de Lapuente Portilla, Aitzkoa, Kang, Guolian, Zhang, Yingze, Nouraie, Seyed Mehdi, Gordeuk, Victor R, Gladwin, Mark T, Garrett, Melanie E, Ashley-Koch, Allison, Telen, Marilyn J, Custer, Brian, Kelly, Shannon, DINARDO, CARLA, Sabino, Ester Cerdeira, Loureiro, Paula, Carneiro-Proietti, Anna Barbara, Maximo, Claudia, Mendez, Adriana, Hammerer-Lercher, Angelika, Sheehan, Vivien A, Weiss, Mitchell J, Franke, Lude, Nilsson, Bjorn, Butterworth, Adam S, Viprakasit, Vip, Nkya, Siana, and Sankaran, Vijay G.

Subjects
Article
Abstract

Human genetic variation has enabled the identification of several key regulators of fetal-to-adult hemoglobin switching, including BCL11A, resulting in therapeutic advances. However, despite the progress made, limited further insights have been obtained to provide a fuller accounting of how genetic variation contributes to the global mechanisms of fetal hemoglobin (HbF) gene regulation. Here, we have conducted a multi-ancestry genome-wide association study of 28,279 individuals from several cohorts spanning 5 continents to define the architecture of human genetic variation impacting HbF. We have identified a total of 178 conditionally independent genome-wide significant or suggestive variants across 14 genomic windows. Importantly, these new data enable us to better define the mechanisms by which HbF switching occurs in vivo. We conduct targeted perturbations to define BACH2 as a new genetically-nominated regulator of hemoglobin switching. We define putative causal variants and underlying mechanisms at the well-studied BCL11A and HBS1L-MYB loci, illuminating the complex variant-driven regulation present at these loci. We additionally show how rare large-effect deletions in the HBB locus can interact with polygenic variation to influence HbF levels. Our study paves the way for the next generation of therapies to more effectively induce HbF in sickle cell disease and β-thalassemia.

Published
2023

3. Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Author

Oddsson, Asmundur, Sulem, Patrick, Sveinbjornsson, Gardar, Arnadottir, Gudny A., Steinthorsdottir, Valgerdur, Halldorsson, Gisli H., Atlason, Bjarni A., Oskarsson, Gudjon R., Helgason, Hannes, Nielsen, Henriette Svarre, Westergaard, David, Karjalainen, Juha M., Katrinardottir, Hildigunnur, Fridriksdottir, Run, Jensson, Brynjar O., Tragante, Vinicius, Ferkingstad, Egil, Jonsson, Hakon, Gudjonsson, Sigurjon A., Beyter, Doruk, Moore, Kristjan H. S., Thordardottir, Helga B., Kristmundsdottir, Snaedis, Stefansson, Olafur A., Rantapää-Dahlqvist, Solbritt, Sonderby, Ida Elken, Didriksen, Maria, Stridh, Pernilla, Haavik, Jan, Tryggvadottir, Laufey, Frei, Oleksandr, Walters, G. Bragi, Kockum, Ingrid, Hjalgrim, Henrik, Olafsdottir, Thorunn A., Selbaek, Geir, Nyegaard, Mette, Erikstrup, Christian, Brodersen, Thorsten, Saevarsdottir, Saedis, Olsson, Tomas, Nielsen, Kaspar Rene, Haraldsson, Asgeir, Bruun, Mie Topholm, Hansen, Thomas Folkmann, Brunak, Søren, Nielsen, Kasper Rene, Brun, Mie Topholm, Gudbjartsson, Daniel, Stefánsson, Hreinn, Þorsteinsdóttir, Unnur, Steingrimsdottir, Thora, Jacobsen, Rikke Louise, Lie, Rolv T., Djurovic, Srdjan, Alfredsson, Lars, Lopez de Lapuente Portilla, Aitzkoa, Brunak, Soren, Melsted, Pall, Halldorsson, Bjarni V., Saemundsdottir, Jona, Magnusson, Olafur Th., Padyukov, Leonid, Banasik, Karina, Rafnar, Thorunn, Askling, Johan, Klareskog, Lars, Pedersen, Ole Birger, Masson, Gisli, Havdahl, Alexandra, Nilsson, Bjorn, Andreassen, Ole A., Daly, Mark, Ostrowski, Sisse Rye, Jonsdottir, Ingileif, Holm, Hilma, Helgason, Agnar, Thorsteinsdottir, Unnur, Stefansson, Kari, and Gudbjartsson, Daniel F.

Subjects
Medical Genetics, Medicinsk genetik
Abstract

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785. Correction: Oddsson, A., Sulem, P., Sveinbjornsson, G. et al. Publisher Correction: Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality. Nat Commun 14, 3923 (2023). DOI: 10.1038/s41467-023-39492-4

Published
2023

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