Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

被引：51

作者：

Chami, Nathalie ^{[1
,2
]}

Chen, Ming-Huei ^{[3
]}

Slater, Andrew J. ^{[4
,5
]}

Eicher, John D. ^{[3
]}

Evangelou, Evangelos ^{[6
,7
]}

Tajuddin, Salman M. ^{[8
]}

Love-Gregory, Latisha ^{[9
]}

Kacprowski, Tim ^{[10
,11
]}

Schick, Ursula M. ^{[12
]}

Nomura, Akihiro ^{[13
,14
,15
,16
,17
]}

Giri, Ayush ^{[18
]}

Lessard, Samuel ^{[1
,2
]}

Brody, Jennifer A. ^{[19
]}

Schurmann, Claudia ^{[12
,20
]}

Pankratz, Nathan ^{[21
]}

Yanek, Lisa R. ^{[22
]}

Manichaikul, Ani ^{[23
]}

Pazoki, Raha ^{[24
]}

Mihailov, Evelin ^{[25
]}

Hill, W. David ^{[26
,27
]}

Raffield, Laura M. ^{[28
]}

Burt, Amber ^{[29
]}

Bartz, Traci M. ^{[30
]}

Becker, Diane M. ^{[22
]}

Becker, Lewis C. ^{[31
]}

Boerwinkle, Eric ^{[32
,33
]}

Bork-Jensen, Jette ^{[34
]}

Bottinger, Erwin P. ^{[12
]}

O'Donoghue, Michelle L. ^{[35
]}

Crosslin, David R. ^{[36
]}

de Denus, Simon ^{[2
,37
]}

Dube, Marie-Pierre ^{[1
,2
]}

Elliott, Paul ^{[6
]}

Engstrom, Gunnar ^{[38
,39
]}

Evans, Michele K. ^{[8
]}

Floyd, James S. ^{[19
]}

Fornage, Myriam ^{[40
]}

Gao, He ^{[6
]}

Greinacher, Andreas ^{[41
]}

Gudnason, Vilmundur ^{[42
,43
]}

Hansen, Torben ^{[34
]}

Harris, Tamara B. ^{[44
]}

Hayward, Caroline ^{[45
]}

Hernesniemi, Jussi ^{[46
,47
,48
]}

Highland, Heather M. ^{[32
,49
]}

Hirschhorn, Joel N. ^{[14
,50
]}

Hofman, Albert ^{[24
,51
]}

Irvin, Marguerite R. ^{[52
]}

Kahonen, Mika ^{[53
,54
]}

Lange, Ethan ^{[55
,56
]}

机构：

[1] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada

[2] Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada

[3] NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA

[4] GlaxoSmithKline, Genet Target Sci, Res Triangle Pk, Res Triangle Pk, NC 27709 USA

[5] OmicSoft Corp, Cary, NC 27513 USA

[6] Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England

[7] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina 45110, Greece

[8] NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA

[9] Washington Univ, Sch Med, Dept Med, Ctr Human Nutr, St Louis, MO 63110 USA

[10] Univ Greifswald, Dept Funct Gen, Interfaculty Inst Genet & Funct Gen, Univ Med, D-17475 Greifswald, Germany

[11] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany

[12] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10069 USA

[13] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[14] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[15] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[16] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[17] Kanazawa Univ, Grad Sch Med Sci, Div Cardiovasc Med, Kanazawa, Ishikawa 9200942, Japan

[18] Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Genet Inst, Div Epidemiol, Nashville, TN 37235 USA

[19] Univ Washington, Dept Med, Seattle, WA 98101 USA

[20] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10069 USA

[21] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA

[22] Johns Hopkins Univ, Sch Med, Dept Med Div Gen Internal Med icine, Div Gen Internal Med, Baltimore, MD 21205 USA

[23] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA 22908 USA

[24] Erasmus, Dept Epidemiol, NL-3000 Mcrotterdam, Netherlands

[25] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia

[26] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland

[27] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland

[28] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA

[29] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA

[30] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[31] Johns Hopkins Univ Sch Med, Dept Med, Div Cardiol & Gen Internal Med, Baltimore, MD 21205 USA

[32] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA

[33] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[34] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, DK-2100 Copenhagen, Denmark

[35] Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, Boston, MA 02115 USA

[36] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA

[37] Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada

[38] Lund Univ, Dept Clin Sci, S-22100 Malmo, Sweden

[39] Skane Univ Hosp, S-22241 Malmo, Sweden

[40] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX 77030 USA

[41] Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany

[42] Iceland Heart Assoc, IS-201 Kopavogur, Iceland

[43] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

[44] NIA, Intramural Res Program, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA

[45] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[46] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland

[47] Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland

[48] Univ Tampere, Sch Med, Tampere 33014, Finland

[49] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA

[50] Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2016年 / 99卷 / 01期

关键词：

GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; AFRICAN-AMERICANS; SEQUENCE VARIANTS; PYRUVATE-KINASE; LOW-FREQUENCY; LOCI; RECEPTOR; GENE; METAANALYSIS;

D O I：

10.1016/j.ajhg.2016.05.007

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 x 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 x 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 x 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 x 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.

引用

页码：8 / 21

页数：14

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