rs10512472 (SLFN14): Platelet Count & Volume Variant

Key takeaways

• This variant maps to the SLFN14 (Schlafen Family Member 14) locus, one of 68 genomic regions confirmed to influence platelet count and mean platelet volume
• SLFN14 was validated as a novel regulator of blood cell formation through gene-silencing experiments in zebrafish and fruit flies
• The 68 platelet-associated loci together explain about 4.8% of platelet count variance and 9.9% of mean platelet volume variance
• GTEx eQTL data shows this variant reduces expression of AP2B1 in the heart left ventricle and multiple brain regions, and of PEX12 in three brain areas
• Trans-ethnic analyses across five global populations (n=746,667) confirm directionally consistent platelet associations at this locus

What the research says SLFN14 (Schlafen Family Member 14) was identified among 68 genomic regions reliably associated with platelet count and mean platelet volume (MPV) in a high-powered meta-analysis of up to 66,867 individuals of European ancestry; functional validation through gene silencing in zebrafish and Drosophila melanogaster confirmed it as one of 11 novel regulators of blood cell formation PMID 23202127. The largest blood cell trait GWAS to date identified 5,106 new genetic variants across 29 blood phenotypes in 563,085 European ancestry participants, including novel splice-altering variants at the locus PMID 34289339. Trans-ethnic meta-analyses in 746,667 individuals from five global populations - including 184,535 non-European participants - achieved fine-mapping credible sets 30% smaller than European-only analyses, improving localization of likely causal variants at blood cell loci PMID 34289340.

Reported associations

• Platelet count (PLT): Associated at genome-wide significance (P ≤ 5×10^-8); the 68 PLT loci together explain approximately 4.8% of PLT variance, with per-allele effects averaging ~2.57×10^9 platelets/L across those loci PMID 23202127
• Mean platelet volume (MPV): Also associated at genome-wide significance; the 68 loci together explain approximately 9.9% of MPV variance, with per-allele effects averaging ~0.10 fL PMID 23202127
• Blood cell traits (29-phenotype panel): Included among 5,106 newly identified variants in 563,085 participants; novel splice-altering variants were identified at the locus PMID 34289339
• Trans-ethnic blood cell traits: Examined across 746,667 participants from five population groups; directionally consistent associations observed across ancestry groups, with 85 of 88 testable variant-trait associations confirmed directionally in an independent replication cohort PMID 34289340

Evidence quality The platelet-trait associations at this locus are supported by progressively larger, well-replicated analyses. The original discovery was made in a meta-analysis of up to 66,867 European-ancestry individuals across up to 23 studies, with stage 2 replication in up to 18,838 additional individuals; cross-species functional validation in zebrafish and Drosophila provided independent biological support PMID 23202127. Evidence was substantially extended by the largest blood cell GWAS at the time of publication - 563,085 European ancestry participants across 29 phenotypes - which identified novel splice-altering variants at the locus and characterized the omnigenic architecture of hematopoietic traits PMID 34289339. Trans-ethnic meta-analyses (746,667 participants from African, Admixed American, East Asian, and European ancestry groups) confirmed directional consistency and improved 95% credible set precision by 30% compared to European-only analyses PMID 34289340. Individual locus effect sizes are modest - the full set of 68 platelet loci collectively accounts for only 4.8-9.9% of PLT and MPV phenotypic variance - consistent with the highly polygenic architecture of quantitative blood traits. No direct conflicts between the contributing studies were identified; the progression from smaller to larger, more diverse cohorts represents cumulative confirmatory evidence.

Tissue-specific expression effects

• C17orf50: The ALT allele is associated with increased expression in the nucleus accumbens (a basal ganglia structure) of the brain GTEx Portal
• PEX12 (peroxisome biogenesis factor 12, required for peroxisome assembly): The ALT allele is associated with reduced expression in three brain regions - the cortex, frontal cortex (Brodmann area 9), and hypothalamus - indicating a consistent, broad reduction of this gene across brain subregions GTEx Portal
• AP2B1 (adaptor-related protein complex 2 subunit beta 1, involved in intracellular vesicle trafficking): The ALT allele is associated with reduced expression in the cervical spinal cord, the putamen (basal ganglia), and the heart left ventricle; the heart left ventricle signal is particularly well-supported statistically (p=2.4×10^-8) GTEx Portal
• ENSG00000267592 (uncharacterized locus): The ALT allele is associated with increased expression in tibial artery tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.