Faculty Collaboration Database

Rare coding variants pinpoint genes that control human hematological traits. PLoS Genet 2017 Aug;13(8):e1006925

Date

08/09/2017

Pubmed ID

28787443

Pubmed Central ID

PMC5560754

DOI

10.1371/journal.pgen.1006925

Scopus ID

2-s2.0-85028882963 (requires institutional sign-in at Scopus site)   35 Citations

Abstract

The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.

Author List

Mousas A, Ntritsos G, Chen MH, Song C, Huffman JE, Tzoulaki I, Elliott P, Psaty BM, Blood-Cell Consortium, Auer PL, Johnson AD, Evangelou E, Lettre G, Reiner AP

Author

Paul L. Auer PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Asthma
Databases, Genetic
Endometriosis
Female
Fibrin Fibrinogen Degradation Products
Gene Frequency
Genetic Loci
Genome, Human
Genome-Wide Association Study
Humans
Interleukin-33
Linear Models
Logistic Models
Male
Mutation, Missense
Phenotype
Plasminogen
Platelet Count
Polymorphism, Single Nucleotide
Principal Component Analysis
Protein Splicing
Rhinitis, Allergic
Sequence Analysis, DNA