This month in The Journal

Cross-phenotype associations can arise through pleiotropy, a process by which a single gene influences multiple traits. Vertical pleiotropy occurs when the genetic effect on one trait directly mediates the effect on another trait, whereas horizontal pleiotropy arises when the genetic effect indirectly mediates multiple traits through distinct biological mechanisms. Existing approaches for detecting both vertical and horizontal pleiotropy were largely developed for common variants and cannot determine whether shared gene-level rare variant burden association arises from concordant allelic effects or from distinct variants acting through different mechanisms.