Hiding in plain sight: uncovering the genetic basis of complex phenotypes through low-risk groups
Recommended Citation
Vazquez AI, Li Y, Lu G, Neelam H, Bray MS, Shrestha S, Reynolds RJ, Gui H, Gulisija D. Hiding in Plain Sight: Uncovering the Genetic Basis of Complex Phenotypes through Low-Risk Groups. Genetics. 2026;234(1).
Document Type
Article
Publication Date
9-2-2026
Publication Title
Genetics
Keywords
Humans, Phenotype, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Multifactorial Inheritance, Genetic Predisposition to Disease, UK Biobank
Abstract
Medical genetic studies focus on high-risk groups to enrich for targeted phenotypes. Although genetic effects may vary across the lifespan, age-related enrichment of target phenotypes can also arise from cumulative environmental exposures, without requiring changes in genetic architecture. Accumulating environmental effects over the lifetime can inflate nongenetic variance, creating the illusion of greater genetic signal while in fact masking underlying genetic effects. We propose investigating the genetic architecture of complex phenotypes in lower-risk, younger individuals, which may reduce residual variance and improve power to isolate the genetic underpinnings of complex disease-related traits. To illustrate this, we analyzed 9 complex traits across age-stratified White European cohorts in the UK Biobank. Genome-wide association analyses reveal a greater number of genome-wide significant SNPs in younger cohorts. Complementing these results, heritability analyses show a higher relative genetic contribution in younger cohorts. Together, these patterns demonstrate that genetic signals are more readily detected in lower-risk, younger individuals. This perspective suggests that temporal dynamics in genetic architecture should guide participant selection, challenging the traditional focus on high-risk older groups and highlighting the value of targeting higher-heritability groups for genetic discovery.
Medical Subject Headings
Humans; Phenotype; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Multifactorial Inheritance; Genetic Predisposition to Disease; UK Biobank
PubMed ID
42461975
ePublication
ePub ahead of print
Volume
234
Issue
1
