Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants

Kathryn A. Lawrence; Tamara Gjorgjieva; Daniel Nachun; Stephen B. Montgomery

doi:10.1016/j.ajhg.2026.02.022

March 1, 2026The American Journal of Human GeneticsOpen Access

Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants

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Key Points

The aim is to investigate how neighboring genes share regulatory effects, challenging traditional single-gene assumptions.
Mapped QTLs on expression principal components of co-expressed neighboring genes.
Analyzed regulatory effects beyond single-gene frameworks.
Identified previously overlooked QTLs and GWAS colocalizations.
Discovered new QTLs that were not detected by standard single-gene methods.
Founded evidence of allelic proxitropy among neighboring genes.
Highlighted missed GWAS colocalizations that could enhance variant interpretation.

Implication

Identifies shared regulatory effects in gene expression, suggesting new approaches for variant interpretation.

Abstract

Standard eQTL mapping and GWAS interpretation assume that each variant acts on one gene.However, neighboring genes can exhibit "allelic proxitropy," where regulatory effects are shared.To identify these effects, we map QTLs on expression principal components of co-expressed neighboring genes.We discover QTLs and GWAS colocalizations missed by single-gene methods.

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Cite This Study

Lawrence et al. (2026) studied this question.

synapsesocial.com/papers/69c4cc37fdc3bde448917785 https://doi.org/10.1016/j.ajhg.2026.02.022

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Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants

Key Points

Implication

Abstract

Discussion

Cite This Study

Focus on single-gene effects limits discovery and interpretation of complex-trait-associated variants

Key Points

Implication

Abstract

Discussion

Cite This Study

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