A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function.
Mean platelet volume (MPV) and platelet count (PLT) are highly heritable and tightly regulated traits. We performed a genome-wide association study for MPV and identified one SNP, rs342293, as having highly significant and reproducible association with MPV (per-G allele effect 0.016 +/- 0.001 log fL; P < 1.08 x 10(-24)) and PLT (per-G effect -4.55 +/- 0.80 10(9)/L; P < 7.19 x 10(-8)) in 8586 healthy subjects. Whole-genome expression analysis in the 1-MB region showed a significant association with platelet transcript levels for PIK3CG (n = 35; P = .047). The G allele at rs342293 was also associated with decreased binding of annexin V to platelets activated with collagen-related peptide (n = 84; P = .003). The region 7q22.3 identifies the first QTL influencing platelet volume, counts, and function in healthy subjects. Notably, the association signal maps to a chromosome region implicated in myeloid malignancies, indicating this site as an important regulatory site for hematopoiesis. The identification of loci regulating MPV by this and other studies will increase our insight in the processes of megakaryopoiesis and proplatelet formation, and it may aid the identification of genes that are somatically mutated in essential thrombocytosis.
Soranzo
Nicole
N
Human Genetics Department, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. ns6@sanger.ac.uk
Rendon
Augusto
A
Gieger
Christian
C
Jones
Chris I
CI
Watkins
Nicholas A
NA
Menzel
Stephan
S
Döring
Angela
A
Stephens
Jonathan
J
Prokisch
Holger
H
Erber
Wendy
W
Potter
Simon C
SC
Bray
Sarah L
SL
Burns
Philippa
P
Jolley
Jennifer
J
Falchi
Mario
M
Kühnel
Brigitte
B
Erdmann
Jeanette
J
Schunkert
Heribert
H
Samani
Nilesh J
NJ
Illig
Thomas
T
Garner
Stephen F
SF
Rankin
Angela
A
Meisinger
Christa
C
Bradley
John R
JR
Thein
Swee Lay
SL
Goodall
Alison H
AH
Spector
Tim D
TD
Deloukas
Panos
P
Ouwehand
Willem H
WH
D000328:Adult; D000368:Aged; D001792:Blood Platelets; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D013920:Thrombocythemia, Essential / Q000235:genetics; D034061:Thrombopoiesis / Q000235:genetics*