Table 1. GWAS of PPR and genetic score... | American Society of Hematology

Table 1.

GWAS of PPR and genetic score of general PR

Chr	Position	rsID	Ref	Alt	MAF	P_INTERVAL	β_INTERVAL	SE_INTERVAL	Gene	Comments	CBC associations	β_score	P_score	Phenotype for β_score
1	156869047	rs12566888	G	T	0.10	5.0 × 10^–24	−0.12	0.012	*PEAR1*	Variant is associated with ADP- and epinephrine-induced platelet aggregation.¹¹^,¹² Platelet receptor that signals upon platelet-platelet contact in response to and independently of the activation response.²⁶	PLT, MPV, and PDW	−0.99	3.2 × 10^–8	ADP
1	199010721	rs1434282	C	T	0.27	1.9 × 10^–17	−0.07	0.008	PTPRC	Protein regulates GP6-mediated signaling during platelet activation via Src family kinase.²⁷	PLT, MPV, and PCT	−0.12	4.5 × 10^–3	CRP-XL
1	247712303	rs41315846	T	C	0.47	1.4 × 10^–11	−0.05	0.007	GCSAML	Protein identified as a mediator of platelet activation downstream of cAMP/protein kinase A signaling using protein-protein interaction analysis.²⁸	PLT, MPV, PDW, and PCT	−0.17	1.1 × 10^–3	PAR1
2	224874874	rs13412535	G	A	0.24	2.2 × 10^–10	−0.06	0.009	SERPINE2	Protein is a serine protease inhibitor with activity against the potent platelet activator thrombin.²⁹	MPV	0.07	1.3 × 10^–1	CRP-XL
2	241510903	rs78909033	G	A	0.13	2.5 × 10^–11	−0.07	0.010	RNPEPL1		PLT, MPV, PDW, and PCT	0.10	6.6 × 10^–2	CRP-XL
3	56849749	rs1354034	T	C	0.40	1.2 × 10^–24	−0.07	0.007	*ARHGEF3*	Variant is associated with ADP-induced aggregation.¹⁴ Guanine nucleotide exchanger for ρA, implicated in platelet production and ADP-mediated platelet activation.³⁰	PLT, MPV, PDW, and PCT	−0.64	4.2 × 10^–10	ADP
3	124340093	rs13067286	G	A	0.48	2.2 × 10^–11	0.05	0.007	KALRN	Protein is a ρ-GTPase activator, activated by ADP receptor signaling in platelets.³¹ Another variant in KALRN (rs3772800) is associated with the risk of myocardial infarction.³²	PLT, MPV, and PDW	−0.14	4.9 × 10^–3	PAR1
3	124366890	rs76445378	C	T	0.02	5.8 × 10^–⁹	−0.17	0.029	KALRN		PLT, MPV, and PDW	−0.41	8.4 × 10^–2	PAR1
5	122088890	rs922140	A	G	0.40	9.4 × 10^–21	0.07	0.007	SNX2		MPV and PCT	−0.08	1.3 × 10^–1	PAR1
6	31322694	rs3819288†	T	C	0.10	1.2 × 10^–12	−0.08	0.012	HLA-B	Antigen-presenting major histocompatibility complex class I molecule that mediates alloimmune clearance of circulating platelets.³³ Other variants in this region are associated with unstable angina pectoris,³⁴ myocardial infarction, use of antithrombotic agents,³⁵ and rheumatoid arthritis,³⁶ among many other phenotypes.	PLT and MPV	0.19	1.8 × 10^–3	PAR4
9	99234329	rs55665228	C	T	0.19	4.0 × 10^–11	−0.06	0.009	HABP4		PLT, MPV, PDW, and PCT	−0.35	1.2 × 10^–2	ADP
9	113312231	rs61751937	G	C	0.03	9.2 × 10^–16	0.17	0.021	*SVEP1*∗	Gene recently associated with ADP-induced platelet aggregation using a gene-based approach.¹⁵ Extracellular matrix protein that interacts with PEAR1 to activate platelets.³⁷	PLT, MPV, and PDW	1.45	8.2 × 10^–6	ADP
10	121010256	rs10886430	A	G	0.14	2.3 × 10^–10	0.07	0.011	*GRK5*	Variant is associated with thrombin-induced platelet aggregation and VTE.¹⁰^,¹⁴ The protein is a serine/threonine kinase GPCR regulator that modulates thrombin-mediated platelet activation.¹⁴	PLT, MPV, and PDW	0.90	2.8 × 10^–40	PAR1
11	10711817	rs7123827	A	C	0.50	7.2 × 10^–10	0.04	0.007	*IRAG1*	Other variants in this region are associated with ADP- and epinephrine-induced platelet aggregation.¹¹^,¹² Inositol 1,45-triphosphate receptor regulator during nitric oxide/cyclic GMP modulation of PR.³⁸	PLT and MPV	0.05	1.7 × 10^–1	CRP-XL
12	122216910	rs11553699	A	G	0.15	4.2 × 10^–35	0.13	0.011	RHOF	Variant is associated with serum levels of heparin-binding EGF.³⁹ Small GTPase actin regulator that mediates platelet filopodia formation.⁴⁰	PLT, MPV, PDW, and PCT	0.06	3.2 × 10^–1	CRP-XL
14	70653758	rs61978213	G	A	0.05	2.4 × 10^–12	0.12	0.018	SLC8A3	Protein is a sodium/calcium exchanger involved in platelet calcium homeostasis.⁴¹ Another variant near gene (rs55784307) is associated with peripheral arterial disease.⁴²^,⁴³		0.20	5.9 × 10^–2	PAR4
15	65160392	rs59001897✝	T	A	0.18	6.4 × 10^–⁹	0.05	0.010	PLEKHO2	Another variant near PLEKHO2 (rs832890) is associated with pulse pressure.⁴⁴	PLT, MPV, PDW, and PCT	0.15	2.8 × 10^–1	ADP
16	9052989	rs8057254	T	A	0.19	2.8 × 10^–⁹	0.05	0.009	USP7	Inhibition of USP7 blocks collagen-stimulated aggregation.⁴⁵	PLT, MPV, and PDW	0.10	3.4 × 10^–2	CRP-XL
16	81870969	rs12445050	C	T	0.14	5.2 × 10^–25	0.11	0.010	PLCG2	Variant associated with VTE⁴⁶ and CAD.³⁴ Protein is a member of the phospholipase C family and mediates GP6- and α_IIbβ₃-mediated platelet activation.⁴⁷	PLT, MPV, and PDW	0.09	1.0 × 10^–1	CRP-XL
17	3819002	rs11078475	T	C	0.47	2.5 × 10^–10	0.05	0.007	P2RX1	Gene is overexpressed in reticulated platelets.⁴⁸ Protein is a platelet ATP receptor contributing to platelet granule release.⁴⁹	PLT and MPV	0.16	1.1 × 10^–1	ADP
19	55538980	rs1654425	T	C	0.17	3.7 × 10^–22	0.09	0.009	*GP6*	A variant in strong LD (rs1671152) is associated with collagen-induced platelet aggregation mediated by the surface receptor encoded by GP6.¹² The protein is a platelet receptor for the potent activating agonist collagen.	PLT, MPV, and PDW	0.89	5.4 × 10^–100	CRP-XL

Chr	Position	rsID	Ref	Alt	MAF	P_INTERVAL	β_INTERVAL	SE_INTERVAL	Gene	Comments	CBC associations	β_score	P_score	Phenotype for β_score
1	156869047	rs12566888	G	T	0.10	5.0 × 10^–24	−0.12	0.012	*PEAR1*	Variant is associated with ADP- and epinephrine-induced platelet aggregation.¹¹^,¹² Platelet receptor that signals upon platelet-platelet contact in response to and independently of the activation response.²⁶	PLT, MPV, and PDW	−0.99	3.2 × 10^–8	ADP
1	199010721	rs1434282	C	T	0.27	1.9 × 10^–17	−0.07	0.008	PTPRC	Protein regulates GP6-mediated signaling during platelet activation via Src family kinase.²⁷	PLT, MPV, and PCT	−0.12	4.5 × 10^–3	CRP-XL
1	247712303	rs41315846	T	C	0.47	1.4 × 10^–11	−0.05	0.007	GCSAML	Protein identified as a mediator of platelet activation downstream of cAMP/protein kinase A signaling using protein-protein interaction analysis.²⁸	PLT, MPV, PDW, and PCT	−0.17	1.1 × 10^–3	PAR1
2	224874874	rs13412535	G	A	0.24	2.2 × 10^–10	−0.06	0.009	SERPINE2	Protein is a serine protease inhibitor with activity against the potent platelet activator thrombin.²⁹	MPV	0.07	1.3 × 10^–1	CRP-XL
2	241510903	rs78909033	G	A	0.13	2.5 × 10^–11	−0.07	0.010	RNPEPL1		PLT, MPV, PDW, and PCT	0.10	6.6 × 10^–2	CRP-XL
3	56849749	rs1354034	T	C	0.40	1.2 × 10^–24	−0.07	0.007	*ARHGEF3*	Variant is associated with ADP-induced aggregation.¹⁴ Guanine nucleotide exchanger for ρA, implicated in platelet production and ADP-mediated platelet activation.³⁰	PLT, MPV, PDW, and PCT	−0.64	4.2 × 10^–10	ADP
3	124340093	rs13067286	G	A	0.48	2.2 × 10^–11	0.05	0.007	KALRN	Protein is a ρ-GTPase activator, activated by ADP receptor signaling in platelets.³¹ Another variant in KALRN (rs3772800) is associated with the risk of myocardial infarction.³²	PLT, MPV, and PDW	−0.14	4.9 × 10^–3	PAR1
3	124366890	rs76445378	C	T	0.02	5.8 × 10^–⁹	−0.17	0.029	KALRN		PLT, MPV, and PDW	−0.41	8.4 × 10^–2	PAR1
5	122088890	rs922140	A	G	0.40	9.4 × 10^–21	0.07	0.007	SNX2		MPV and PCT	−0.08	1.3 × 10^–1	PAR1
6	31322694	rs3819288†	T	C	0.10	1.2 × 10^–12	−0.08	0.012	HLA-B	Antigen-presenting major histocompatibility complex class I molecule that mediates alloimmune clearance of circulating platelets.³³ Other variants in this region are associated with unstable angina pectoris,³⁴ myocardial infarction, use of antithrombotic agents,³⁵ and rheumatoid arthritis,³⁶ among many other phenotypes.	PLT and MPV	0.19	1.8 × 10^–3	PAR4
9	99234329	rs55665228	C	T	0.19	4.0 × 10^–11	−0.06	0.009	HABP4		PLT, MPV, PDW, and PCT	−0.35	1.2 × 10^–2	ADP
9	113312231	rs61751937	G	C	0.03	9.2 × 10^–16	0.17	0.021	*SVEP1*∗	Gene recently associated with ADP-induced platelet aggregation using a gene-based approach.¹⁵ Extracellular matrix protein that interacts with PEAR1 to activate platelets.³⁷	PLT, MPV, and PDW	1.45	8.2 × 10^–6	ADP
10	121010256	rs10886430	A	G	0.14	2.3 × 10^–10	0.07	0.011	*GRK5*	Variant is associated with thrombin-induced platelet aggregation and VTE.¹⁰^,¹⁴ The protein is a serine/threonine kinase GPCR regulator that modulates thrombin-mediated platelet activation.¹⁴	PLT, MPV, and PDW	0.90	2.8 × 10^–40	PAR1
11	10711817	rs7123827	A	C	0.50	7.2 × 10^–10	0.04	0.007	*IRAG1*	Other variants in this region are associated with ADP- and epinephrine-induced platelet aggregation.¹¹^,¹² Inositol 1,45-triphosphate receptor regulator during nitric oxide/cyclic GMP modulation of PR.³⁸	PLT and MPV	0.05	1.7 × 10^–1	CRP-XL
12	122216910	rs11553699	A	G	0.15	4.2 × 10^–35	0.13	0.011	RHOF	Variant is associated with serum levels of heparin-binding EGF.³⁹ Small GTPase actin regulator that mediates platelet filopodia formation.⁴⁰	PLT, MPV, PDW, and PCT	0.06	3.2 × 10^–1	CRP-XL
14	70653758	rs61978213	G	A	0.05	2.4 × 10^–12	0.12	0.018	SLC8A3	Protein is a sodium/calcium exchanger involved in platelet calcium homeostasis.⁴¹ Another variant near gene (rs55784307) is associated with peripheral arterial disease.⁴²^,⁴³		0.20	5.9 × 10^–2	PAR4
15	65160392	rs59001897✝	T	A	0.18	6.4 × 10^–⁹	0.05	0.010	PLEKHO2	Another variant near PLEKHO2 (rs832890) is associated with pulse pressure.⁴⁴	PLT, MPV, PDW, and PCT	0.15	2.8 × 10^–1	ADP
16	9052989	rs8057254	T	A	0.19	2.8 × 10^–⁹	0.05	0.009	USP7	Inhibition of USP7 blocks collagen-stimulated aggregation.⁴⁵	PLT, MPV, and PDW	0.10	3.4 × 10^–2	CRP-XL
16	81870969	rs12445050	C	T	0.14	5.2 × 10^–25	0.11	0.010	PLCG2	Variant associated with VTE⁴⁶ and CAD.³⁴ Protein is a member of the phospholipase C family and mediates GP6- and α_IIbβ₃-mediated platelet activation.⁴⁷	PLT, MPV, and PDW	0.09	1.0 × 10^–1	CRP-XL
17	3819002	rs11078475	T	C	0.47	2.5 × 10^–10	0.05	0.007	P2RX1	Gene is overexpressed in reticulated platelets.⁴⁸ Protein is a platelet ATP receptor contributing to platelet granule release.⁴⁹	PLT and MPV	0.16	1.1 × 10^–1	ADP
19	55538980	rs1654425	T	C	0.17	3.7 × 10^–22	0.09	0.009	*GP6*	A variant in strong LD (rs1671152) is associated with collagen-induced platelet aggregation mediated by the surface receptor encoded by GP6.¹² The protein is a platelet receptor for the potent activating agonist collagen.	PLT, MPV, and PDW	0.89	5.4 × 10^–100	CRP-XL

The first 10 columns show the results of the GWAS of a PR phenotype predicted from Sysmex scattergrams in INTERVAL. The coordinates are given with respect to genome build GRCh37. The subsequent columns include (1) a comment on each gene mapped to the associated single nucleotide polymorphism, (2) a list of CBC trait associations identified previously by GWAS,⁵⁰ and (3) the effect size and P value corresponding to the PR trait with the smallest P value for association in the PFC and the agonist corresponding to that trait. The bold gene names indicate loci previously associated with a PR phenotype by GWAS analysis (P < 5 × 10^–8) or, in the case of SVEP1, by gene-based analysis (P < 10^–5). The underlined gene names indicate associations with evidence for replication in partial summary statistics from LTA studies (P < 3 × 10^–4).^10,15

Alt, alternate allele; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; Chr, chromosome; EGF, epidermal growth factor; GMP, guanosine monophosphate; GPCR, G protein-coupled receptor; GTP, guanosine triphosphate; MAF, minor allele frequency; MPV, mean platelet volume; PCT, platelet crit; PLT, platelet count; PDW, platelet distribution width; Ref, reference allele; SE, standard error.

∗

Locus previously associated with a PR phenotype by gene-based analysis using the significance threshold P < 10⁻⁵.

†

Because statistics summarizing the associations in the PFC between PR phenotypes and these variants were not available, we identified suitable proxies in the PFC to build a genetic score (supplemental Table 3).

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