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.

中文翻译：

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存在异质效应的情况下家庭 GWAS 的因果解释


基于家庭的全基因组关联研究 (GWAS) 通常被认为可以根据等位基因从父母到子女的随机传播之间的类比，提供对等位基因的平均因果效应（或平均治疗效应；ATE）的无偏估计。儿童和随机对照试验。我们证明这种说法一般来说并不成立。由于孟德尔分离仅随机化杂合子子女中的等位基因，因此无法观察到等位基因对纯合子子女的影响。如果等位基因在纯合子和杂合子的后代中具有不同的平均效应，则该特征将很重要，因为在存在基因与环境相互作用、基因与基因相互作用或连锁不平衡模式差异的情况下可能会出现这种情况。在单个位点，基于家庭的 GWAS 可以被认为提供了对杂合子儿童平均效果的无偏估计（即局部平均治疗效果；LATE）。然而，这种解释并不适用于多基因评分 (PGS)，因为每个家族中不同的 SNP 组都是杂合的。因此，除了在特定条件下之外，不能假设 PGS 的家庭内回归斜率为任何家庭子集或加权平均值提供 LATE 的无偏估计。在实践中，基于家庭的 GWAS 的潜在偏差可能小于标准的、基于人群的 GWAS 中的混​​杂可能产生的偏差，因此家庭研究对于剖析遗传对表型变异的贡献仍然很重要。尽管如此，他们的因果解释并不像人们普遍认为的那么简单。