ArticleProceedings of the National Academy of Sciences of the United States of America2024
Causal interpretations of family GWAS in the presence of heterogeneous effects.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed.
- Genomic insights into natural selection in recent human history.Nature reviews. Genetics · 2026Review
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- 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
- A quantitative genetic model for indirect genetic effects and genomic imprinting under random and assortative mating.Genetics · 2026Article
- Brain Structure and Substance Use: Disentangling Risk, Exposure, and Drug-Specific Effects.medRxiv : the preprint server for health sciences · 2026Article
- Representation in genetic studies affects inference about genetic architecture.bioRxiv : the preprint server for biology · 2026Article
- Hidden structure in polygenic scores and the challenge of disentangling ancestry interactions in admixed populations.Genetics · 2025Article
- The genetic lottery goes to school: Better schools compensate for the effects of students' genetic differences.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference.Research square · 2025Article
- Genotypic and socioeconomic risks for depressive symptoms in two U.S. cohorts spanning early to older adulthood.Journal of psychopathology and clinical science · 2025Article
- An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference.bioRxiv : the preprint server for biology · 2025Article
- No More Free Lunch: Challenges to Mendelian Randomization Due to Sample Selection and Complex Methods.The Journal of clinical endocrinology and metabolism · 2025Article
- Social and Behavioral Genomics: On the Ethics of the Research and Its Downstream Applications.Annual review of genomics and human genetics · 2025Review
- Evaluating ARG-estimation methods in the context of estimating population-mean polygenic score histories.Genetics · 2025Article
- Article
- Tradeoffs in Modeling Context Dependency in Complex Trait Genetics.bioRxiv : the preprint server for biology · 2025Article
- A Litmus Test for Confounding in Polygenic Scores.bioRxiv : the preprint server for biology · 2025Article
- Using the phenotype differences model to identify genetic effects in samples of partially genotyped sibling pairs.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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Abstract
Family-based genome-wide association studies (GWASs) are often claimed to provide an unbiased estimate of the average causal effects (or average treatment effects; ATEs) of alleles, on the basis of an analogy between the random transmission of alleles from parents to children and a randomized controlled trial. We show that this claim does not hold in general. Because Mendelian segregation only randomizes alleles among children of heterozygotes, the effects of alleles in the children of homozygotes are not observable. This feature will matter if an allele has different average effects in the children of homozygotes and heterozygotes, as can arise in the presence of gene-by-environment interactions, gene-by-gene interactions, or differences in linkage disequilibrium patterns. At a single locus, family-based GWAS can be thought of as providing an unbiased estimate of the average effect in the children of heterozygotes (i.e., a local average treatment effect; LATE). This interpretation does not extend to polygenic scores (PGSs), however, because different sets of SNPs are heterozygous in each family. Therefore, other than under specific conditions, the within-family regression slope of a PGS cannot be assumed to provide an unbiased estimate of the LATE for any subset or weighted average of families. In practice, the potential biases of a family-based GWAS are likely smaller than those that can arise from confounding in a standard, population-based GWAS, and so family studies remain important for the dissection of genetic contributions to phenotypic variation. Nonetheless, their causal interpretation is less straightforward than has been widely appreciated.
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