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SMIM1

Summary

SMIM1 encodes small integral membrane protein 1, a transmembrane protein that underlies the Vel blood group. Variation at the locus includes an expression quantitative trait locus and a frameshift variant responsible for the Vel-negative blood type, and the region is associated with multiple aspects of red-blood-cell biology [1].

Genetic Context

The flashfmZero protocol analyzes a chromosome 1 interval from 3,441,528 to 3,959,487 around SMIM1. Four latent blood-trait factors showed genome-wide significant regional associations, and joint multivariate latent-factor fine-mapping prioritized rs1175550 (chr1_3691528) as the single variant in every factor's 95% credible set.[1]

The factor contribution patterns connect the locus with mean corpuscular hemoglobin concentration, red-cell-distribution and macrocyte measures, and reticulocyte fluorescence and maturity traits. These associations are consistent with a broad role in erythrocyte biology but do not by themselves prove that every statistical association acts through the same molecular mechanism.

Fine-Mapping Evidence

In the primary 18,310-person analysis, observed red-cell trait 99% credible sets containing rs1175550 had 30-58 variants and single-factor latent sets had 5-27 variants. Joint flashfmZero assigned rs1175550 an MPP above 0.99 and reduced the credible set for each of ML4, ML12 and ML14 to that one variant.[4]

UK Biobank fine-mapping independently prioritized rs1175550 for nine red-cell traits. Published molecular evidence identifies it as an intronic SMIM1 expression QTL and a modulator of Vel blood-group antigen expression, connecting the statistical signal to gene regulation.[4]

Citations

[1] Astle, Butterworth and Asimit (2025), flashfmZero protocol and SMIM1 example [2] Cvejic et al. (2013), "SMIM1 underlies the Vel blood group and influences red blood cell traits" [3] Storry et al. (2013), "Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype" [4] Zhou et al. (2025), latent-factor discovery and fine-mapping study