Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.

Authors:
Nathalie Chami Ming-Huei Chen Andrew J Slater John D Eicher Evangelos Evangelou Salman M Tajuddin Latisha Love-Gregory Tim Kacprowski Ursula M Schick Akihiro Nomura Ayush Giri Samuel Lessard Jennifer A Brody Claudia Schurmann Nathan Pankratz Lisa R Yanek Ani Manichaikul Raha Pazoki Evelin Mihailov W David Hill Laura M Raffield Amber Burt Traci M Bartz Diane M Becker Lewis C Becker Eric Boerwinkle Jette Bork-Jensen Erwin P Bottinger Michelle L O'Donoghue David R Crosslin Simon de Denus Marie-Pierre Dubé Paul Elliott Gunnar Engström Michele K Evans James S Floyd Myriam Fornage He Gao Andreas Greinacher Vilmundur Gudnason Torben Hansen Tamara B Harris Caroline Hayward Jussi Hernesniemi Heather M Highland Joel N Hirschhorn Albert Hofman Marguerite R Irvin Mika Kähönen Ethan Lange Lenore J Launer Terho Lehtimäki Jin Li David C M Liewald Allan Linneberg Yongmei Liu Yingchang Lu Leo-Pekka Lyytikäinen Reedik Mägi Rasika A Mathias Olle Melander Andres Metspalu Nina Mononen Mike A Nalls Deborah A Nickerson Kjell Nikus Chris J O'Donnell Marju Orho-Melander Oluf Pedersen Astrid Petersmann Linda Polfus Bruce M Psaty Olli T Raitakari Emma Raitoharju Melissa Richard Kenneth M Rice Fernando Rivadeneira Jerome I Rotter Frank Schmidt Albert Vernon Smith John M Starr Kent D Taylor Alexander Teumer Betina H Thuesen Eric S Torstenson Russell P Tracy Ioanna Tzoulaki Neil A Zakai Caterina Vacchi-Suzzi Cornelia M van Duijn Frank J A van Rooij Mary Cushman Ian J Deary Digna R Velez Edwards Anne-Claire Vergnaud Lars Wallentin Dawn M Waterworth Harvey D White James G Wilson Alan B Zonderman Sekar Kathiresan Niels Grarup Tõnu Esko Ruth J F Loos Leslie A Lange Nauder Faraday Nada A Abumrad Todd L Edwards Santhi K Ganesh Paul L Auer Andrew D Johnson Alexander P Reiner Guillaume Lettre

Am J Hum Genet 2016 Jul 23;99(1):8-21. Epub 2016 Jun 23.

Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Montreal Heart Institute, Montréal, QC H1T 1C8, Canada. Electronic address:

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2016.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005438PMC
July 2016
151 Reads

Publication Analysis

Top Keywords

blood cell
12
red blood
8
variants associated
8
rare missense
8
rbc variants
8
missense variants
8
rare low-frequency
8
associated lower
8
variants
7
associated
7
rbc
5
traits
5
mendelian mutations
4
identified rare
4
10-9 mendelian
4
missense variant
4
rare
4
mutations alas2
4
differentiated human
4
human erythroblasts
4

Similar Publications