Parent-of-Origin inference for biobanks

Identical genetic variations can have different phenotypic effects depending on their parent of origin. Yet, studies focusing on parent-of-origin effects have been limited in terms of sample size due to the lack of parental genomes or known genealogies. We propose a probabilistic approach to infer t...

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Bibliographic Details
Published in:Nature communications Vol. 13; no. 1; pp. 6668 - 15
Main Authors: Hofmeister, Robin J., Rubinacci, Simone, Ribeiro, Diogo M., Buil, Alfonso, Kutalik, Zoltán, Delaneau, Olivier
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 05.11.2022
Nature Publishing Group
Nature Portfolio
Subjects:
45
45/43
631/114/2397
631/208/176/1968
631/208/205/2138
Alleles
Biobanks
Biological Specimen Banks
Biomarkers
Body mass index
Body size
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2
Female
Genealogy
Genetic diversity
Genome-Wide Association Study
Genomes
Haplotypes
Heritability
Humanities and Social Sciences
Humans
Inference
Male
Molecular modelling
multidisciplinary
Phenotype
Phenotypes
Phenotypic variations
Preadipocyte factor 1
Science
Science (multidisciplinary)
Telomeres
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Identical genetic variations can have different phenotypic effects depending on their parent of origin. Yet, studies focusing on parent-of-origin effects have been limited in terms of sample size due to the lack of parental genomes or known genealogies. We propose a probabilistic approach to infer the parent-of-origin of individual alleles that does not require parental genomes nor prior knowledge of genealogy. Our model uses Identity-By-Descent sharing with second- and third-degree relatives to assign alleles to parental groups and leverages chromosome X data in males to distinguish maternal from paternal groups. We combine this with robust haplotype inference and haploid imputation to infer the parent-of-origin for 26,393 UK Biobank individuals. We screen 99 phenotypes for parent-of-origin effects and replicate the discoveries of 6 GWAS studies, confirming signals on body mass index, type 2 diabetes, standing height and multiple blood biomarkers, including the known maternal effect at the MEG3/DLK1 locus on platelet phenotypes. We also report a novel maternal effect at the TERT gene on telomere length, thereby providing new insights on the heritability of this phenotype. All our summary statistics are publicly available to help the community to better characterize the molecular mechanisms leading to parent-of-origin effects and their implications for human health. Studies on parent-of-origin effects have been limited in terms of sample size due to lack of parental genomes or known genealogies. Here, the authors develop a method to infer the parent-of-origin of an individual alleles in biobank-scale datasets, without requiring parental genomes or prior knowledge of genealogy, allowing discovery of parent-of-origin effects with an unprecedented sample size.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-34383-6