rs10512627 (KALRN): Platelet Count Variant

Key takeaways

• rs10512627 lies within KALRN, a signaling gene whose region is linked to platelet count in studies of tens of thousands of people.
• All 68 confirmed platelet-count genetic loci combined explain only about 4.8% of platelet count variation, so any single variant contributes a small share.
• The ALT allele at rs10512627 is associated with increased KALRN expression in seven tissues, most strongly in liver.
• Platelet-count genetics can shift during pregnancy: a study of over 100,000 women found some loci have time-varying effects across trimesters.
• The UK Biobank study of 363,228 people found over 10,000 significant locus-biomarker associations and improved genetic risk prediction for common diseases.

What the research says A GWAS meta-analysis in up to 66,867 Europeans identified 68 loci reliably associated with platelet count or mean platelet volume (MPV), with confirmed directional replication in South Asian and Japanese cohorts, and these 68 loci collectively explain 4.8% of platelet count variance and 9.9% of MPV variance, with average per-locus effects of approximately 2.57 x 10^9 platelets per liter and 0.10 fL per allele copy for MPV. PMID 22139419 A systematic analysis of 35 blood and urine biomarkers in 363,228 UK Biobank participants identified 1,857 loci with fine-mapped associations and derived polygenic scores that improved disease risk stratification for kidney disease, type 2 diabetes, gout, and liver cirrhosis in an independent cohort of 135,500. PMID 33462484 GTEx v11 expression data (953 donors) show that the rs10512627 ALT allele is associated with increased KALRN expression in seven tissues, with the largest effect in liver (slope +0.45), and with increased expression of a neighboring gene (ENSG00000304375) in tibial artery. GTEx Portal

Reported associations

• Platelet count: KALRN-region variants are among 68 genome-wide significant loci for platelet count in a European-ancestry meta-analysis of up to 66,867 individuals, with per-locus effects averaging approximately 2.57 x 10^9 platelets per liter per allele copy and direction of effect consistent in South Asian and Japanese replication samples. PMID 22139419
• Mean platelet volume (MPV): The same meta-analysis identified loci for MPV, with 68 confirmed loci together explaining 9.9% of MPV variance and averaging approximately 0.10 fL per allele copy; the two traits show a negative correlation (r = -0.49), reflecting tight control of total platelet mass. PMID 22139419
• Blood biomarker traits (UK Biobank): Among 35 biomarkers analyzed in 363,228 UK Biobank participants, 1,857 associated loci were identified with over 10,000 significant variant-trait associations; platelet-related traits were among those studied, and Mendelian Randomization analyses uncovered 51 causal biomarker-to-disease relationships. PMID 33462484
• Platelet count during pregnancy: A GWAS of platelet counts at five time-points across pregnancy in 100,186 Chinese women identified 138 genome-wide significant loci explaining 10.4% to 12.1% of platelet count variation, with evidence that genetic effects for certain variants shift in magnitude from the first trimester through the postpartum period, a time-specific pattern not previously described at this scale.
• KALRN tissue-specific expression (eQTL): The rs10512627 ALT allele is associated with increased KALRN expression in liver (+0.45), pancreas (+0.25), adrenal gland (+0.22), esophagus mucosa (+0.20), stomach (+0.20), thyroid (+0.19), and skeletal muscle (+0.16), all at FDR below 0.05 in GTEx v11. GTEx Portal

Evidence quality The platelet-trait GWAS evidence PMID 22139419 rests on a multi-stage meta-analysis: stage 1 in up to 66,867 Europeans across 23 studies (platelet count) and 18,600 across 13 studies (MPV), followed by in silico and de novo replication in up to 18,838 individuals across 12 additional studies, all at p at or below 5 x 10^-8. Cross-ethnic replication in South Asian (n=14,697) and Japanese (n=8,295) cohorts showed directionally consistent effects in more than 80% of loci, a degree of concordance highly unlikely by chance (p = 2.3 x 10^-12 for South Asian, p = 2.1 x 10^-6 for Japanese). The UK Biobank analysis PMID 33462484 provides a large independent replication context at n=363,228 with a Bonferroni-corrected threshold of p below 5 x 10^-9 for imputed variants. The pregnancy GWAS (100,186 Chinese women, five time-points) adds evidence of time-varying genetic effects on platelet counts but does not describe KALRN-specific results in the available text. The GTEx eQTL evidence (953 donors, FDR-controlled, cis-window) is the most direct mechanistic link to KALRN function at rs10512627. Individual locus effect sizes for platelet traits are uniformly modest: all 68 loci combined explain under 5% of platelet count variance, so any single variant accounts for a small fraction of that. No conflicting findings were identified across the provided evidence, though the studies differ in ancestry (European-predominant vs. Chinese) and context (general population vs. pregnancy).

Tissue-specific expression effects

• KALRN: The ALT allele is associated with increased KALRN expression in liver (largest effect), pancreas, adrenal gland, esophagus mucosa, stomach, thyroid, and skeletal muscle, all meeting FDR below 0.05 in GTEx v11 (953 donors). These expression changes represent a mechanistic signal, not a direct measure of clinical outcomes. GTEx Portal
• ENSG00000304375: The ALT allele is associated with increased expression of this neighboring locus in tibial artery. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.