Family Analysis with Mendelian Imputations
Open accessAbstract
Genotype-phenotype associations can be results of direct effects, genetic nurturing effects and population stratification confounding. Genotypes from parents and siblings of the proband can be used to statistically disentangle these effects. To maximize power, a comprehensive framework for utilizing various combinations of parents’ and siblings’ genotypes is introduced. Central to the approach is mendelian imputation , a method that utilizes identity by descent (IBD) information to non-linearly impute genotypes into untyped relatives using genotypes of typed individuals. Applying the method to UK Biobank probands with at least one parent or sibling genotyped, for an educational attainment (EA) polygenic score that has an R 2 of 5.7% with EA, its predictive power based on direct genetic effect alone is demonstrated to be only about 1.4%. For women, the EA polygenic score has a bigger estimated direct effect on age-at-first-birth than EA itself.
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Sibling effects have been estimated to be modest compared with parental effects but could have impacted the GWAS estimates.
“Sibling effects have been estimated to be modest compared with parental effects6,48 but could have impacted our GWAS estimates.”
From Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects (2022) · cites this paper as [48]
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References 21 · Cited by 15
Research works printed but not linked: 4
- Liu, J. Z., Erlich, Y. & Pickrell, J. K. Case--control association mapping by proxy using family history of disease. Nat. Genet. 49, 325 (2017).
- Brumpton, B. et al. Within-family studies for Mendelian randomization: avoiding dynastic, assortative mating, and population stratification biases. bioRxiv (2019) doi:10.1101/602516. · DOI
- Hwang, L.-D. et al. Estimating indirect parental genetic effects on offspring phenotypes using virtual parental genotypes derived from sibling and half sibling pairs. BioRxiv (2020).
- Mills, M. C., Tropf, F. C., Brazel, D. M., Zuydam, N. Van & Vaez, A. Identification of 370 loci for age at onset of sexual and reproductive behaviour, highlighting common aetiology with reproductive biology, externalizing behaviour and longevity. BioRxiv (2020).
- Authors
- Kong, A., Benonisdottir, S., & Young, A. I.
- Affiliations
- University of Oxford (GB)
- University of Southern California (US)
- Corresponding author
- Kong, Augustine
- Young, Alexander I.
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-07-03
- OpenAlex
- W3040661431
- Cited by
- 15
- References
- 21
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 8 · 2021: 4
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- Funders
- Li Ka Shing Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- genotype-phenotype correlation, direct genetic effects, population stratification, identity by descent, parents and siblings, educational attainment, polygenic risk score, age at first birth, UK Biobank
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