ArticlePLoS biology2024
Interpreting population- and family-based genome-wide association studies in the presence of confounding.
Article in PLoS biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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63 citing papers in PubMed.
- Effect of population structure and stabilizing selection on quantitative genetic variation.Genetics · 2026Article
- Estimating direct and indirect genetic effects on emerging variation in depressive symptoms in early adolescence: a trio polygenic score analysis in the MoBa cohort : Author list.European child & adolescent psychiatry · 2026Article
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- "Yet the Problem Remains": Why Genetic Determinism Still Haunts Biomedical Research.Bioethics · 2026Article
- Separating direct, indirect, and parent-of-origin genetic effects in the human population.Cell genomics · 2026Article
- Within-sibling attenuation of polygenic risk score accuracy: investigating the effects of principal component analysis, LD score regression, and mixed model association in the UK Biobank.Human genetics · 2026Article
- A generalized test of genotype-phenotype causality in population-sampled nuclear families.PLoS genetics · 2026Article
- Polygenic scores in psychiatric research and clinical practice.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2026Article
- Estimation of direct and indirect polygenic effects and gene-environment interactions using polygenic scores in case-parent trio studies.Nature genetics · 2026Article
- Evaluating confounding in rare variant genome wide association studies.Nature communications · 2026Article
- Genomic-Relatedness Matching Expands Population Coverage, Improves Power, and Reduces Bias in Genetic Association Analyses.medRxiv : the preprint server for health sciences · 2026Article
- Estimating uncertainty in family-based GWAS.bioRxiv : the preprint server for biology · 2026Article
- Quantifying direct genetic signal captured by principal component adjustment.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Family-Based GWAS of Cognitive Endophenotypes Reveals Genetic Architecture of Memory and Executive Function in Alzheimer's Disease.Current issues in molecular biology · 2026Article
- Estimating returns to education using the genetic lottery.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A quantitative genetic model for indirect genetic effects and genomic imprinting under random and assortative mating.Genetics · 2026Article
- Dissecting the Predictive Accuracy of Polygenic Indexes for Behavioral Phenotypes Across Genetic Ancestries.bioRxiv : the preprint server for biology · 2026Article
- The effect of long-range linkage disequilibrium on allele-frequency dynamics under stabilizing selection.PLoS genetics · 2026Article
- Personality Genomics.Annual review of psychology · 2026Review
3 more citing papers are in PubMed but not listed here.
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Abstract
A central aim of genome-wide association studies (GWASs) is to estimate direct genetic effects: the causal effects on an individual's phenotype of the alleles that they carry. However, estimates of direct effects can be subject to genetic and environmental confounding and can also absorb the "indirect" genetic effects of relatives' genotypes. Recently, an important development in controlling for these confounds has been the use of within-family GWASs, which, because of the randomness of mendelian segregation within pedigrees, are often interpreted as producing unbiased estimates of direct effects. Here, we present a general theoretical analysis of the influence of confounding in standard population-based and within-family GWASs. We show that, contrary to common interpretation, family-based estimates of direct effects can be biased by genetic confounding. In humans, such biases will often be small per-locus, but can be compounded when effect-size estimates are used in polygenic scores (PGSs). We illustrate the influence of genetic confounding on population- and family-based estimates of direct effects using models of assortative mating, population stratification, and stabilizing selection on GWAS traits. We further show how family-based estimates of indirect genetic effects, based on comparisons of parentally transmitted and untransmitted alleles, can suffer substantial genetic confounding. We conclude that, while family-based studies have placed GWAS estimation on a more rigorous footing, they carry subtle issues of interpretation that arise from confounding.
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