Locus/Trait	Description of most likely functional SNP
GFI1B/PLT	Index SNP (iSNP) rs150813342 is a synonymous variant altering a predicted GFI1B exon 5 splice site. GFI1B is a transcription factor involved in the regulation of red cell and platelet production 34. Rare, heterozygous LoF mutations of GFI1B have been reported in hereditary thrombocytopenia [OMIM #187900]. rs150813342 has no LD proxies and it is predicted to be causative by CAVIARBF (PP=1). Furthermore, it lies within a region enriched for H3K4me1 and H3k36me3 in megakaryocytes 52.
NPRL3/MCH	iSNP rs117747069 is a low-frequency intronic variant of NPRL3 with no LD proxies, predicted as the most likely causal variant (CAVIARBF PP=0.84) and conditionally independent of the common NPRL3 variant rs11248850 previously associated with MCH 8. NPRL3 is known to contain nucleosome-depleted regions involved in the regulation of the alpha-globin genes on chr 16 8. rs117747069 is located in erythroid-specific super-enhancer 53 54,55,52, which is hypersensitive, enriched for H3K27ac marks in erythroblasts, and overlapping ChIP-Seq signal for erythroid transcription factors GATA-1, GATA-2 and TAL-1 in K562 cells 56. While the nearest gene NPRL3 is a potential target of the enhancer element, chromatin interactions in K562 cells 56 suggest that the super-enhancer element interacts with several downstream genes including HBA1 and HBA2.
CCND3/MCV	iSNP rs112233623 is a low-frequency intronic variant of CCND3, conditionally independent of the previously reported common association of rs9349204 with red cell traits8. Cyclin D3 plays a critical role in cell cycle regulation. The iSNP is located within an erythroid-specific enhancer 37,55,52 enriched for H3K27ac mark in erythroblasts and is bound by GATA-2 and TAL1 in K562 cells 56. Its association with hemoglobin A2 levels 36 also supports the role of this variant in the regulation of alpha-globin.
HLA-DRA/WBC	Index variant rs113164910 is a 2 bp indel lying in the class II MHC region, 14 kb 3’ of HLA-DRA. The most likely fSNP rs9268781 (8 kb 3’ of HLA-DR) is a strong eQTL for various HLA-DR and –DQ genes in blood 57 and overlaps a DNaseI hypersensitive (DHS) site in blood monocytes 58. Another LD proxy rs7763262 has been previously associated with IgA nephropathy 59.
HLA-B/WBC	iSNP rs2442735 is located ~20 kb 5’ of the HLA-B locus and is conditionally independent of another HLA-B intronic SNP in the class I MHC region rs2853946 associated with WBC 60. The most likely fSNP rs2853999, 1 kb 5’ of HLA-B, is a blood eQTL for HLA-C, C4A, and C4B and overlaps blood cell promoter and enhancer, DNase and histone marks. A proxy SNP has been associated with marginal zone lymphoma 61.
THPO/PLT	iSNP rs78565404 is a second THPO signal, conditionally independent of the previously reported platelet GWAS variant rs6141 62. Both SNPs fall in the 3’ UTR and have no LD proxies. THPO is a key regulator of platelet production. THPO gain-of-function mutations have been identified in hereditary thrombocythemia [OMIM #187950]. rs78565404 binds the transcription factor MAFK (ChIPSeq in HepG2 cells), a component of the NF-E2 complex involved in erythropoiesis and megakaryopoiesis 38,39.
GCSAML/PLT	iSNP rs41315846 is located in a hematopoietic cell-lineage specific promoter of GCSAML (C1orf150) 58. It is conditionally independent of previously reported GCSAML intronic iSNP rs7550918 and has no LD proxies. GCSAML encodes a protein thought to be a signaling molecule associated with germinal centers, the sites of proliferation and differentiation of mature B lymphocytes. rs41315846 lies within a putative enhancer overlapping DHS site, RUNX1, GATA1 and FLI1 ChIP-Seq peaks and H3k27ac enriched region in megakaryocytes 52.
FABP6/PLT	iSNP rs2546979 is a common intronic variant of FABP6, which encodes a fatty acid binding protein not known to play a role in platelet biology. It lies in a region of high LD spanning the region 5’ to the first intron of FABP6. The most likely fSNP (r2=0.7) rs2546372 (located ~22kb upstream of FABP6) overlaps regions enriched for H3k4me1 and H3k27ac signal in megakaryocytes, DNase, RUNX1, and FLI1 ChIP-Seq peaks 52. Another gene in this region, the transcription factor gene PTTG1 is highly expressed in bone marrow stem cells 63 and in megakaryocytes and erythroid precursors. Platelet promoter capture data from Blueprint shows that rs2546979 physically interacts with neighbouring gene CCNJL, which belongs to the family of cyclin genes involved in cell cycle regulation. The presence of H3K27ac (active promoter/enhancer) in the CCNJL promoter region and H3K36me3 (elongation) marks in the body of this gene indicates CCNJL is actively expressed in megakaryocytes 52.
TRABD-MOV10L1/ PLT	iSNP rs75570992 is intronic to MOV10L1, a predicted RNA helicase of unknown function. It is predicted to be causal (CAVIARBF PP=1) and associated with expression of the neighbouring gene TRABD in transformed fibroblasts, colon, and lymphoblastoid cells 57,33. However, another likely fSNP is proxy SNP rs75107793 (r2=0.5), which overlaps promoter and enhancer histone marks in many cell types 58, but more importantly, is located in a putative enhancer overlapping RUNX1 ChIP-Seq and DHS site and H3K4me1 enriched region in megakaryocytes 52. fSNP rs75107793 is also located within a DHS peak in erythroblasts, and lies upstream of TRABD promoter (GENCODE, FANTOM5). Based on RNA-Seq and epigenetic marks (H3K27ac, H3K4me3, H3H36me3), TRABD is expressed in megakaryocytes 52.
ZNF311/WBC	iSNP rs3130725 is located in an intergenic region on chromosome 6 containing extensive LD (>50 proxy SNPs [r2>0.8]), all of which (including rs3130725) are whole blood eQTLs for several genes in the region of class I HLA, including ZFP57, HLA-F, and HLA-H 57. The most likely fSNP is rs3129794, which is located in the promoter region of ZNF311 and overlaps an active promoter in K562 cells 58.
APOH/PLT	iSNP rs1801689 encodes a Cys325Arg amino acid substitution of APOH, also known as beta2-glycoprotein I, a platelet phospholipid-binding protein. It is the most likely fSNP (PP = 0.37 by CAVIARBF), though another proxy SNP rs8178824 (r2=1; PP = 0.22) is located in a liver-specific promoter (Roadmap). Platelet promoter capture data (BLUEPRINT) shows that rs1801689 physically interacts with neighbouring gene PRKCA (protein kinase C alpha), which also plays a role in platelet function and platelet production in mouse models of megakaryopoiesis 64,65.
S1PR3/PLT	iSNP rs61750929 is located ~100kb upstream of S1PR3, which encodes a receptor for sphingosine 1-phosphate (S1P) and likely contributes to the regulation of angiogenesis and vascular endothelial cell function.66,67. S1PR3 overlaps with C9orf47, a gene of unknown function. The iSNP has 33 strong LD proxies, in an inter-genic region between MIR4289 and S1PR3/C9orf47, several of which are cis-eQTLs for S1PR3 in whole blood 68 positioned within megakaryocytic DHS sites (rs62549698, rs9410336) or H3K4Me1-enriched enhancer regions (rs9410196, rs142550358, rs9410336) 52. Two lower LD (r2=0.5) proxies are synonymous (rs11795137) or 3’ UTR variants (rs62551536) of C9orf47.
RASSF3/PLT	iSNP rs113373353 and all 33 of its proxies are intronic to RASSF3, a tumor suppressor that also promotes apoptosis. The most likely fSNP rs77164989 (r2=0.8) lies within a putative enhancer that overlaps with DNase, H3K4me1, and RUNX1 ChIP-Seq peaks in megakaryocytes 52.
SHROOM3/HCT	iSNP rs10008637 is intronic to SHROOM3, which encodes a protein that binds and regulates the subcellular distribution of F-actin 69. An intronic LD proxy rs13146355 of SHROOM3 is associated with lower serum creatinine 20 and higher serum magnesium 21. Another LD proxy (r2=0.8), rs17319721, overlaps DHS sites in endothelial cells and is located in a TCF7L2-dependent enhancer increasing SHROOM3 transcription and influencing TGF-β1 signaling and renal function70.
ABCA1/HDL	The ABCA1 intronic variant rs3824477 (MAF=0.02) is in strong LD (r2 = 0.94) with ABCA1 missense variant (rs2066718 = p.Val771Leu), previously nominally associated with HDL (P=10-4)23. Both SNPs are independent of the common ABCA1 iSNP rs1883025 for HDL 71 and the secondary ABCA1 signal rs11789603 72. ABCA1 regulates cholesterol and phospholipid homeostasis. Rare loss-of-function variants of ABCA1 are associated with Tangier’s disease [OMIM #205400].
TP53BP1/PLT	Index variant chr15:43703277 is a 1bp intronic indel of TP53BP1 located at a DHS site and binding site for several hematopoietic transcription factors including MAFK, GATA1, GATA2, and TAL1. A chromosomal aberration involving TP53BP1 is found in a form of myeloproliferative disorder with eosinophilia 73. The translocation t(5;15)(q33;q22) with PDGFRB creates a TP53BP1-PDGFRB fusion protein.
SLC2A9/Uric acid	iSNP rs56223908 (MAF=0.08) is intronic to the urate transporter SLC2A9 74. It has no LD proxies and it is conditionally independent of the more common, known SLC2A9 uric acid GWAS variant rs12498742 75. Rare mutations in SLC2A9 are a cause of autosomal recessive renal hypouricemia-2 [OMIM #612076]. The iSNP overlaps H3K4me1 enhancer histone marks in several Roadmap cells/tissues (blood, adrenal, muscle, heart, and lung) and is predicted as an active promoter in pancreas.