Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

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Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

Tajuddin, Salman M. (författare): NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA.

Schick, Ursula M. (författare): Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.

Eicher, John D. (författare): NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA.

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Chami, Nathalie (författare): Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.

Giri, Ayush (författare): Vanderbilt Univ, Div Epidemiol, Inst Med & Publ Hlth, Nashville, TN 37235 USA.

Brody, Jennifer A. (författare): Univ Washington, Dept Med, Seattle, WA 98101 USA.

Hill, W. David (författare): Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.

Kacprowski, Tim (författare): Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, D-17475 Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany.

Li, Jin (författare): Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94305 USA.

Lyytikainen, Leo-Pekka (författare): Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland.

Manichaikul, Ani (författare): Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA.

Mihailov, Evelin (författare): Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.

O'Donoghue, Michelle L. (författare): Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA.

Pankratz, Nathan (författare): Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA.

Pazoki, Raha (författare): Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands.

Polfus, Linda M. (författare): Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.

Smith, Albert Vernon (författare): Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.

Schurmann, Claudia (författare): Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.

Vacchi-Suzzi, Caterina (författare): SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA.

Waterworth, Dawn M. (författare): GlaxoSmithKline, Target Sci, Genet, King Of Prussia, PA 19406 USA.

Evangelou, Evangelos (författare): Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.;Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece.

Yanek, Lisa R. (författare): Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA.

Burt, Amber (författare): Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA.

Chen, Ming-Huei (författare): NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA.

van Rooij, Frank J. A. (författare): Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands.

Floyd, James S. (författare): Univ Washington, Dept Med, Seattle, WA 98101 USA.

Greinacher, Andreas (författare): Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany.

Harris, Tamara B. (författare): NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA.

Highland, Heather M. (författare): Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA.

Lange, Leslie A. (författare): Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA.

Liu, Yongmei (författare): Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA.

Magi, Reedik (författare): Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.

Nalls, Mike A. (författare): NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA.

Mathias, Rasika A. (författare): Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA.

Nickerson, Deborah A. (författare): Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98105 USA.

Nikus, Kjell (författare): Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland.;Univ Tampere, Sch Med, Tampere 33014, Finland.

Starr, John M. (författare): Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland.

Tardif, Jean-Claude (författare): Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.

Tzoulaki, Ioanna (författare): Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.;Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece.

Edwards, Digna R. Velez (författare): Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Vanderbilt Epidemiol Ctr,Dept Obstet & Gynecol, Nashville, TN 37203 USA.

Wallentin, Lars (författare): Uppsala universitet,Kardiologi,Uppsala kliniska forskningscentrum (UCR)

Bartz, Traci M. (författare): Univ Washington, Dept Biostat, Seattle, WA 98195 USA.

Becker, Lewis C. (författare): Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA.

Denny, Joshua C. (författare): Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37203 USA.

Raffield, Laura M. (författare): Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA.

Rioux, John D. (författare): Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.

Friedrich, Nele (författare): DZHK German Ctr Cardiovasc Res, Greifswald, Germany.;Univ Med Greifswald, Inst Clin Chem & Lab Med, D-13347 Greifswald, Germany.

Fornage, Myriam (författare): Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA.

Gao, He (författare): Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.

Hirschhorn, Joel N. (författare): Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA.

Liewald, David C. M. (författare): Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.

Rich, Stephen S. (författare): Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA.

Uitterlinden, Andre (författare): Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands.;Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands.;NCHA, NL-3015 GD Rotterdam, Netherlands.

Bastarache, Lisa (författare): Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37203 USA.

Becker, Diane M. (författare): Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA.

Boerwinkle, Eric (författare): Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.

de Denus, Simon (författare): Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada.

Bottinger, Erwin P. (författare): Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.

Hayward, Caroline (författare): Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland.

Hofman, Albert (författare): Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands.;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.

Homuth, Georg (författare): Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, D-17475 Greifswald, Germany.

Lange, Ethan (författare): Univ N Carolina, Dept Genet & Biostat, Chapel Hill, NC 27599 USA.

Launer, Lenore J. (författare): NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA.

Lehtimaki, Terho (författare): Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland.

Lu, Yingchang (författare): Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.

Metspalu, Andres (författare): Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.

O'Donnell, Chris J. (författare): NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.;Boston Vet Adm Healthcare, Cardiol Sect, Boston, MA 02118 USA.;Boston Vet Adm Healthcare, Ctr Populat Genom, Boston, MA 02118 USA.

Quarells, Rakale C. (författare): Morehouse Sch Med, Social Epidemiol Res Ctr, Cardiovasc Res Inst, Atlanta, GA 30310 USA.

Richard, Melissa (författare): Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA.

Torstenson, Eric S. (författare): Vanderbilt Univ, Div Epidemiol, Inst Med & Publ Hlth, Nashville, TN 37235 USA.

Taylor, Kent D. (författare): Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA.

Vergnaud, Anne-Claire (författare): Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.

Zonderman, Alan B. (författare): NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA.

Crosslin, David R. (författare): Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA.

Deary, Ian J. (författare): Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.

Dorr, Marcus (författare): DZHK German Ctr Cardiovasc Res, Greifswald, Germany.;Univ Med Greifswald, Dept Cardiol, D-17475 Greifswald, Germany.

Elliott, Paul (författare): Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.

Evans, Michele K. (författare): NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA.

Gudnason, Vilmundur (författare): Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.

Kahonen, Mika (författare): Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland.

Psaty, Bruce M. (författare): Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA.;Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98101 USA.;Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA.

Rotter, Jerome I. (författare): Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA.

Slater, Andrew J. (författare): OmicSoft Corp, Cary, NC 27513 USA.;GlaxoSmithKline, Genet Target Sci, Res Triangle Pk, NC 27709 USA.

Dehghan, Abbas (författare): Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands.

White, Harvey D. (författare): Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand.;Univ Auckland, Auckland 1142, New Zealand.

Ganesh, Santhi K. (författare): Univ Michigan, Dept Internal Med, Ann Arbor, MI 48108 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48108 USA.

Loos, Ruth J. F. (författare): Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.

Esko, Tonu (författare): Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.

Faraday, Nauder (författare): Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA.

Wilson, James G. (författare): Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA.

Cushman, Mary (författare): Univ Vermont, Dept Med, Div Hematol Oncol, Colchester, VT 05446 USA.

Johnson, Andrew D. (författare): NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA.

Edwards, Todd L. (författare): Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Div Epidemiol,Dept Med, Nashville, TN 37203 USA.

Zakai, Neil A. (författare): Univ Vermont, Dept Med, Div Hematol Oncol, Colchester, VT 05446 USA.

Lettre, Guillaume (författare): Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.

Reiner, Alex P. (författare): Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.

Auer, Paul L. (författare): Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA.

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NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. (creator_code:org_t)

2016
2016
Engelska.
Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 99:1, s. 22-39

Relaterad länk:: https://doi.org/10.1...

Tidskriftsartikel (refereegranskat)

Abstract Ämnesord

Stäng

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of similar to 157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3 ' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.