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

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


Title: Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
Author: DBDS Genomic Consortium
Date: 2023-06-10
Language: English
Scope: 2282915
University/Institute: Reykjavik University
School: Health Sciences
Department: Faculty of Industrial Engineering, Mechanical Engineering and Computer Science
Faculty of Medicine
Other departments
Clinical Laboratory Services, Diagnostics and Blood Bank
Faculty of Sociology, Anthropology and Folkloristics
Series: Nature Communications; 14(1)
ISSN: 2041-1723
DOI: 10.1038/s41467-023-38951-2
Subject: Barnalæknisfræði; Humans; Animals; Mice; Homozygote; Genotype; Proteins/genetics; Genes, Recessive; General Physics and Astronomy; General Chemistry; General Biochemistry,Genetics and Molecular Biology
URI: https://hdl.handle.net/20.500.11815/4249

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Citation:

DBDS Genomic Consortium 2023 , ' Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality ' , Nature Communications , vol. 14 , no. 1 , 3453 , pp. 3453 . https://doi.org/10.1038/s41467-023-38951-2

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.

Description:

Funding Information: We thank the individuals who participated in this study and whose contributions made this work possible. We also thank our valued colleagues at the Icelandic Patient Recruitment Center and the deCODE genetics core facilities who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. We want to acknowledge the FinnGen study ( https://www.finngen.fi/en ) and the UK Biobank for providing genotypic data. We want to acknowledge the participants and investigators of DBDS which is a part of the Bio and Genome Bank Denmark funded by the Danish Regions and has received a grant from the Independent Research Fund Denmark (271-08-0640). We want to acknowledge the participants and investigators of MoBa which is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. Financial support from the Research Council of Norway (223273, 273291, 324252, 274611), South-Eastern Norway Regional Health Authority (#2020060, #2020022), European Union’s Horizon2020 Research and Innovation Programme (CoMorMent project; Grant #847776), Kristian Gerhard Jebsen Stiftelsen (SKGJ-MED-021), and candy’s Foundation is acknowledged. Funding Information: Norwegian genotype data were obtained from both hospital and population-based samples. Clinical samples included data from the DemGene and TOP studies which consist of case control samples of neuropsychiatric disorders. Written informed consent was obtained, and the Regional Committee for Medical and Health Research Ethics (REC) South East (#2009/2485) and Mid Norway (#2014/631) approved the studies. Population-based samples included data from the Norwegian Mother, Father and Child cohort study (Mor og Barn; MoBa) and the Hordaland Health Study (HUSK). MoBa is a population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health. Participants were recruited from all over Norway from 1999–2008. The women provided consent to participation in 41% of the pregnancies. The cohort includes approximately 114,500 children, 95,200 mothers and 75,200 fathers. Blood samples were obtained from both parents during pregnancy and from mothers and children (umbilical cord) at birth. For a more detailed description of the MoBa sample see Magnus et al.. The current study included genotype data from 168,000 mothers, fathers and offspring. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency and approval from the REC. The MoBa cohort is currently regulated by the Norwegian Health Registry Act. Written informed consent was obtained from all mothers and fathers participating in MoBa. The current study was approved by REC South East (#2016/1226). MoBa is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. The HUSK Study is a community-based prospective study conducted in Hordaland County in Norway ( http://husk.b.uib.no ). The project was approved by REC (Western Norway 2018/915), and written informed consent was obtained from all participants. Genotypic data was provided by the HARVEST collaboration (supported by the Research Council of Norway (RCN) (#229624), the NORMENT Centre (RCN #223273) South East Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen; in collaboration with deCODE Genetics, and the Center for Diabetes Research at the University of Bergen (funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the RCN, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities). , Publisher Copyright: © 2023, The Author(s).

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