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

Salman M. Tajuddin, Ursula M. Schick, John D. Eicher, Nathalie Chami, Ayush Giri, Jennifer A. Brody, W. David Hill, Tim Kacprowski, Jin Li, Leo Pekka Lyytikäinen, Ani Manichaikul, Evelin Mihailov, Michelle L. O'Donoghue, Nathan Pankratz, Raha Pazoki, Linda M. Polfus, Albert Vernon Smith, Claudia Schurmann, Caterina Vacchi-Suzzi, Dawn M. WaterworthEvangelos Evangelou, Lisa Yanek, Amber Burt, Ming Huei Chen, Frank J A van Rooij, James S. Floyd, Andreas Greinacher, Tamara B. Harris, Heather M. Highland, Leslie A. Lange, Yongmei Liu, Reedik Mägi, Mike A. Nalls, Rasika Mathias, Deborah A. Nickerson, Kjell Nikus, John M. Starr, Jean Claude Tardif, Ioanna Tzoulaki, Digna R. Velez Edwards, Lars Wallentin, Traci M. Bartz, Lewis Becker, Joshua C. Denny, Laura M. Raffield, John D. Rioux, Nele Friedrich, Myriam Fornage, He Gao, Joel N. Hirschhorn, David C M Liewald, Stephen S. Rich, Andre Uitterlinden, Lisa Bastarache, Diane M Becker, Eric Boerwinkle, Simon de Denus, Erwin P. Bottinger, Caroline Hayward, Albert Hofman, Georg Homuth, Ethan Lange, Lenore J. Launer, Terho Lehtimäki, Yingchang Lu, Andres Metspalu, Chris J. O'Donnell, Rakale C. Quarells, Melissa Richard, Eric S. Torstenson, Kent D. Taylor, Anne Claire Vergnaud, Alan B. Zonderman, David R. Crosslin, Ian J. Deary, Marcus Dörr, Paul Elliott, Michele K. Evans, Vilmundur Gudnason, Mika Kähönen, Bruce M. Psaty, Jerome I. Rotter, Andrew J. Slater, Abbas Dehghan, Harvey D. White, Santhi K. Ganesh, Ruth J F Loos, Tõnu Esko, Nauder Faraday, James G. Wilson, Mary Cushman, Andrew D. Johnson, Todd L. Edwards, Neil A. Zakai, Guillaume Lettre, Alex P. Reiner, Paul L. Auer

Research output: Contribution to journalArticle

Abstract

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 ∼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.

Original languageEnglish (US)
Pages (from-to)22-39
Number of pages18
JournalAmerican Journal of Human Genetics
Volume99
Issue number1
DOIs
StatePublished - Jul 7 2016

Fingerprint

Exome
Immune System Diseases
Leukocyte Count
Autoimmune Diseases
Leukocytes
Hematopoiesis
Neutrophils
Lymphoid Progenitor Cells
Myeloid Progenitor Cells
Centrosome
Mutation
Basophils
Hematologic Diseases
3' Untranslated Regions
Adaptive Immunity
Cell Lineage
Hematopoietic Stem Cells
Eosinophils
Innate Immunity
Microtubules

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. / Tajuddin, Salman M.; Schick, Ursula M.; Eicher, John D.; Chami, Nathalie; Giri, Ayush; Brody, Jennifer A.; Hill, W. David; Kacprowski, Tim; Li, Jin; Lyytikäinen, Leo Pekka; Manichaikul, Ani; Mihailov, Evelin; O'Donoghue, Michelle L.; Pankratz, Nathan; Pazoki, Raha; Polfus, Linda M.; Smith, Albert Vernon; Schurmann, Claudia; Vacchi-Suzzi, Caterina; Waterworth, Dawn M.; Evangelou, Evangelos; Yanek, Lisa; Burt, Amber; Chen, Ming Huei; van Rooij, Frank J A; Floyd, James S.; Greinacher, Andreas; Harris, Tamara B.; Highland, Heather M.; Lange, Leslie A.; Liu, Yongmei; Mägi, Reedik; Nalls, Mike A.; Mathias, Rasika; Nickerson, Deborah A.; Nikus, Kjell; Starr, John M.; Tardif, Jean Claude; Tzoulaki, Ioanna; Velez Edwards, Digna R.; Wallentin, Lars; Bartz, Traci M.; Becker, Lewis; Denny, Joshua C.; Raffield, Laura M.; Rioux, John D.; Friedrich, Nele; Fornage, Myriam; Gao, He; Hirschhorn, Joel N.; Liewald, David C M; Rich, Stephen S.; Uitterlinden, Andre; Bastarache, Lisa; Becker, Diane M; Boerwinkle, Eric; de Denus, Simon; Bottinger, Erwin P.; Hayward, Caroline; Hofman, Albert; Homuth, Georg; Lange, Ethan; Launer, Lenore J.; Lehtimäki, Terho; Lu, Yingchang; Metspalu, Andres; O'Donnell, Chris J.; Quarells, Rakale C.; Richard, Melissa; Torstenson, Eric S.; Taylor, Kent D.; Vergnaud, Anne Claire; Zonderman, Alan B.; Crosslin, David R.; Deary, Ian J.; Dörr, Marcus; Elliott, Paul; Evans, Michele K.; Gudnason, Vilmundur; Kähönen, Mika; Psaty, Bruce M.; Rotter, Jerome I.; Slater, Andrew J.; Dehghan, Abbas; White, Harvey D.; Ganesh, Santhi K.; Loos, Ruth J F; Esko, Tõnu; Faraday, Nauder; Wilson, James G.; Cushman, Mary; Johnson, Andrew D.; Edwards, Todd L.; Zakai, Neil A.; Lettre, Guillaume; Reiner, Alex P.; Auer, Paul L.

In: American Journal of Human Genetics, Vol. 99, No. 1, 07.07.2016, p. 22-39.

Research output: Contribution to journalArticle

Tajuddin, SM, Schick, UM, Eicher, JD, Chami, N, Giri, A, Brody, JA, Hill, WD, Kacprowski, T, Li, J, Lyytikäinen, LP, Manichaikul, A, Mihailov, E, O'Donoghue, ML, Pankratz, N, Pazoki, R, Polfus, LM, Smith, AV, Schurmann, C, Vacchi-Suzzi, C, Waterworth, DM, Evangelou, E, Yanek, L, Burt, A, Chen, MH, van Rooij, FJA, Floyd, JS, Greinacher, A, Harris, TB, Highland, HM, Lange, LA, Liu, Y, Mägi, R, Nalls, MA, Mathias, R, Nickerson, DA, Nikus, K, Starr, JM, Tardif, JC, Tzoulaki, I, Velez Edwards, DR, Wallentin, L, Bartz, TM, Becker, L, Denny, JC, Raffield, LM, Rioux, JD, Friedrich, N, Fornage, M, Gao, H, Hirschhorn, JN, Liewald, DCM, Rich, SS, Uitterlinden, A, Bastarache, L, Becker, DM, Boerwinkle, E, de Denus, S, Bottinger, EP, Hayward, C, Hofman, A, Homuth, G, Lange, E, Launer, LJ, Lehtimäki, T, Lu, Y, Metspalu, A, O'Donnell, CJ, Quarells, RC, Richard, M, Torstenson, ES, Taylor, KD, Vergnaud, AC, Zonderman, AB, Crosslin, DR, Deary, IJ, Dörr, M, Elliott, P, Evans, MK, Gudnason, V, Kähönen, M, Psaty, BM, Rotter, JI, Slater, AJ, Dehghan, A, White, HD, Ganesh, SK, Loos, RJF, Esko, T, Faraday, N, Wilson, JG, Cushman, M, Johnson, AD, Edwards, TL, Zakai, NA, Lettre, G, Reiner, AP & Auer, PL 2016, 'Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases', American Journal of Human Genetics, vol. 99, no. 1, pp. 22-39. https://doi.org/10.1016/j.ajhg.2016.05.003
Tajuddin, Salman M. ; Schick, Ursula M. ; Eicher, John D. ; Chami, Nathalie ; Giri, Ayush ; Brody, Jennifer A. ; Hill, W. David ; Kacprowski, Tim ; Li, Jin ; Lyytikäinen, Leo Pekka ; Manichaikul, Ani ; Mihailov, Evelin ; O'Donoghue, Michelle L. ; Pankratz, Nathan ; Pazoki, Raha ; Polfus, Linda M. ; Smith, Albert Vernon ; Schurmann, Claudia ; Vacchi-Suzzi, Caterina ; Waterworth, Dawn M. ; Evangelou, Evangelos ; Yanek, Lisa ; Burt, Amber ; Chen, Ming Huei ; van Rooij, Frank J A ; Floyd, James S. ; Greinacher, Andreas ; Harris, Tamara B. ; Highland, Heather M. ; Lange, Leslie A. ; Liu, Yongmei ; Mägi, Reedik ; Nalls, Mike A. ; Mathias, Rasika ; Nickerson, Deborah A. ; Nikus, Kjell ; Starr, John M. ; Tardif, Jean Claude ; Tzoulaki, Ioanna ; Velez Edwards, Digna R. ; Wallentin, Lars ; Bartz, Traci M. ; Becker, Lewis ; Denny, Joshua C. ; Raffield, Laura M. ; Rioux, John D. ; Friedrich, Nele ; Fornage, Myriam ; Gao, He ; Hirschhorn, Joel N. ; Liewald, David C M ; Rich, Stephen S. ; Uitterlinden, Andre ; Bastarache, Lisa ; Becker, Diane M ; Boerwinkle, Eric ; de Denus, Simon ; Bottinger, Erwin P. ; Hayward, Caroline ; Hofman, Albert ; Homuth, Georg ; Lange, Ethan ; Launer, Lenore J. ; Lehtimäki, Terho ; Lu, Yingchang ; Metspalu, Andres ; O'Donnell, Chris J. ; Quarells, Rakale C. ; Richard, Melissa ; Torstenson, Eric S. ; Taylor, Kent D. ; Vergnaud, Anne Claire ; Zonderman, Alan B. ; Crosslin, David R. ; Deary, Ian J. ; Dörr, Marcus ; Elliott, Paul ; Evans, Michele K. ; Gudnason, Vilmundur ; Kähönen, Mika ; Psaty, Bruce M. ; Rotter, Jerome I. ; Slater, Andrew J. ; Dehghan, Abbas ; White, Harvey D. ; Ganesh, Santhi K. ; Loos, Ruth J F ; Esko, Tõnu ; Faraday, Nauder ; Wilson, James G. ; Cushman, Mary ; Johnson, Andrew D. ; Edwards, Todd L. ; Zakai, Neil A. ; Lettre, Guillaume ; Reiner, Alex P. ; Auer, Paul L. / Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 1. pp. 22-39.
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abstract = "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 ∼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.",
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TY - JOUR

T1 - Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

AU - Tajuddin, Salman M.

AU - Schick, Ursula M.

AU - Eicher, John D.

AU - Chami, Nathalie

AU - Giri, Ayush

AU - Brody, Jennifer A.

AU - Hill, W. David

AU - Kacprowski, Tim

AU - Li, Jin

AU - Lyytikäinen, Leo Pekka

AU - Manichaikul, Ani

AU - Mihailov, Evelin

AU - O'Donoghue, Michelle L.

AU - Pankratz, Nathan

AU - Pazoki, Raha

AU - Polfus, Linda M.

AU - Smith, Albert Vernon

AU - Schurmann, Claudia

AU - Vacchi-Suzzi, Caterina

AU - Waterworth, Dawn M.

AU - Evangelou, Evangelos

AU - Yanek, Lisa

AU - Burt, Amber

AU - Chen, Ming Huei

AU - van Rooij, Frank J A

AU - Floyd, James S.

AU - Greinacher, Andreas

AU - Harris, Tamara B.

AU - Highland, Heather M.

AU - Lange, Leslie A.

AU - Liu, Yongmei

AU - Mägi, Reedik

AU - Nalls, Mike A.

AU - Mathias, Rasika

AU - Nickerson, Deborah A.

AU - Nikus, Kjell

AU - Starr, John M.

AU - Tardif, Jean Claude

AU - Tzoulaki, Ioanna

AU - Velez Edwards, Digna R.

AU - Wallentin, Lars

AU - Bartz, Traci M.

AU - Becker, Lewis

AU - Denny, Joshua C.

AU - Raffield, Laura M.

AU - Rioux, John D.

AU - Friedrich, Nele

AU - Fornage, Myriam

AU - Gao, He

AU - Hirschhorn, Joel N.

AU - Liewald, David C M

AU - Rich, Stephen S.

AU - Uitterlinden, Andre

AU - Bastarache, Lisa

AU - Becker, Diane M

AU - Boerwinkle, Eric

AU - de Denus, Simon

AU - Bottinger, Erwin P.

AU - Hayward, Caroline

AU - Hofman, Albert

AU - Homuth, Georg

AU - Lange, Ethan

AU - Launer, Lenore J.

AU - Lehtimäki, Terho

AU - Lu, Yingchang

AU - Metspalu, Andres

AU - O'Donnell, Chris J.

AU - Quarells, Rakale C.

AU - Richard, Melissa

AU - Torstenson, Eric S.

AU - Taylor, Kent D.

AU - Vergnaud, Anne Claire

AU - Zonderman, Alan B.

AU - Crosslin, David R.

AU - Deary, Ian J.

AU - Dörr, Marcus

AU - Elliott, Paul

AU - Evans, Michele K.

AU - Gudnason, Vilmundur

AU - Kähönen, Mika

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Slater, Andrew J.

AU - Dehghan, Abbas

AU - White, Harvey D.

AU - Ganesh, Santhi K.

AU - Loos, Ruth J F

AU - Esko, Tõnu

AU - Faraday, Nauder

AU - Wilson, James G.

AU - Cushman, Mary

AU - Johnson, Andrew D.

AU - Edwards, Todd L.

AU - Zakai, Neil A.

AU - Lettre, Guillaume

AU - Reiner, Alex P.

AU - Auer, Paul L.

PY - 2016/7/7

Y1 - 2016/7/7

N2 - 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 ∼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.

AB - 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 ∼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.

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

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