328: Variant selection boosts R2 for haptoglobin (HP) in cis‑Mendelian randomization

Zhou A et al., Human Genetics and Genomics Advances - Comparing LD‑pruning, COJO, SuSiE and PCA in haptoglobin (HP) cis‑region data, the study finds including non‑lead variants substantially increases variance explained (R2) and MR precision.

Study Highlights:
The study analyzed circulating haptoglobin (HP) using Fenland protein GWAS summary statistics with LD from UK Biobank, compared four variant selection methods (modified LD‑pruning, COJO, SuSiE, PCA), and extended results with simulations and 15 additional gene regions. In the HP region, incorporating non‑lead variants produced a median proportional gain in R2 of 145.1% and a median reduction in MR standard error of 36.3% relative to the lead variant alone. In simulations with one or two causal variants the methods recovered the expected genetic variance (≈40%) and, when causal variants were removed, non‑lead‑inclusive methods recovered more variance than lead‑only. The functional implication supported by the data is that including correlated non‑lead variants can materially increase instrument strength and precision in cis‑MR, but may raise risks of pleiotropy and numerical instability.

Conclusion:
Variant selection methods that incorporate correlated non‑lead variants reliably improve instrument strength (R2) and MR precision in cis‑MR compared with the lead‑variant‑only approach; comparisons with the lead variant are advised to detect instability.

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Reference:
Zhou A, Karhunen V, Tian H, Pott J, Patel A, Slob EAW, Burgess S. Variant selection to maximize variance explained in cis-Mendelian randomization. Human Genetics and Genomics Advances. 2026 Apr 9;7:100573. https://doi.org/10.1016/j.xhgg.2026.100573.

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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