Abstract

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10−12) and X-linked CLDN2 (P < 1 × 10−21) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).

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Acknowledgements

Technical support was provided by K. Stello, S. Das, D. Dwyer, A. Rowland, P.A. Blake, M. Ross, C. McGovern, L. Kish, H. Nawaz, S. Solomon, S. Boggiano, R. Ostroff, M. Goss and J. Timm. Data management was provided by L. Silfies and D. Protivnak. Clinical support was provided by S. Boggaino, M. Hendricks, B. Elinoff, L. McHenry, G. Lehman, J. Watkins, E. Fogel and L. Lazzell-Pannell. Additional samples were provided by F. Burton (deceased; St. Louis University School of Medicine); S. Lo (Cedars-Sinai Medical Center, University of California, Los Angeles); M.T. DeMeo (Rush University Medical Center); W.M. Steinberg (Washington Hospital Center); M.L. Kochman (University of Pennsylvania); B. Etemad (Ochsner Medical Center); and H. Zeh, A.J. Moser and K.K. Lee (University of Pittsburgh). This publication was made possible by grants R56DK061451 (D.C.W.), R01DK054709 (D.C.W.), T32DK063922 (D.C.W.), R01MH057881 (B.D. and K.R.), R01CA117926 (J.P.S.), R01DK077906 (D.C.W. and D.Y.), UL1RR024153 and UL1TR000005 from the US National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. This project used the University of Pittsburgh Genomics and Proteomics Core Laboratories (UL1RR024153, UL1RR024153 and UL1TR000005) and the University of Pittsburgh Cancer Institute (UPCI) Clinical Genomics Immunoproteomics and Sequencing Facility (NIH P30CA047904). J.L. was supported by Digestive Disease Training Program T32DK063922 (D.C.W.). N.O.Z. was supported by the American Gastroenterology Association John I Isenberg International Scholar Award. The Liverpool cohort was supported by the National Institute for Health Research (NIHR) Biomedical Research Unit award. Additional support was provided by the National Pancreas Foundation (D.C.W.), the Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program (D.C.W.) and the Wayne Fusaro Pancreatic Cancer Research Fund (D.C.W.) and Gift of Life Foundation (J.P.S.).

Support for control cohort 1.

Alzheimer's Disease Genetics Consortium (ADGC): The NIH–National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01AG032984 and RC2AG036528; National Alzheimer's Coordinating Center (NACC), U01AG016976; National Cell Repository for Alzheimer's Disease (NCRAD), U24AG021886; Banner Sun Health Research Institute, P30AG019610; Boston University, P30AG013846, U01AG10483, R01CA129769, R01MH080295, R01AG017173, R01AG025259 and R01AG33193; Columbia University, P50AG008702 and R37AG015473; Duke University, P30AG028377 and AG05128; Emory University, AG025688; Indiana University, P30AG10133; Johns Hopkins University, P50AG005146 and R01AG020688; Massachusetts General Hospital, P50AG005134; Mayo Clinic, P50AG016574; Mount Sinai School of Medicine, P50AG005138 and P01AG002219; New York University, P30AG08051, MO1RR00096 and UL1RR029893; Northwestern University, P30AG013854; Oregon Health & Science University, P30AG008017 and R01AG026916; Rush University, P30AG010161, R01AG019085, R01AG15819, R01AG17917 and R01AG30146; University of Alabama at Birmingham, P50AG016582 and UL1RR02777; University of Arizona, R01AG031581; University of California, Davis, P30AG010129; University of California, Irvine, P50AG016573, P50AG016575, P50AG016576 and P50AG016577; University of California, Los Angeles, P50AG016570; University of California, San Diego, P50AG005131; University of California, San Francisco, P50AG023501 and P01AG019724; University of Kentucky, P30AG028383 and AG05144; University of Michigan, P50AG008671; University of Pennsylvania, P30AG010124; University of Pittsburgh, P50AG005133 and AG030653; University of Southern California, P50AG005142; University of Texas Southwestern, P30AG012300; University of Miami, R01AG027944, AG010491, AG027944, AG021547 and AG019757; University of Washington, P50AG005136; Vanderbilt University, R01AG019085; and Washington University, P50AG005681 and P01AG03991. The Kathleen Price Bryan Brain Bank at the Duke University Medical Center is funded by National Institute of Neurological Disorders and Stroke (NINDS) grant NS39764 and National Institute of Mental Health (NIMH) grant MH60451 and by GlaxoSmithKline. We thank D.S. Snyder and M. Miller who are ex officio ADGC members.

Support for control group 2.

Control group 2 genotypes were obtained from the Genome-Wide Association Study of Parkinson Disease: Genes and Environment, database of Genotypes and Phenotypes (dbGaP) study phs000196.v2.p1. This NeuroGenetics Research Consortium (NGRC) is a gene-environment study of Parkinson's disease. The principal investigator is H. Payami (New York State Department of Health Wadsworth Center, Albany, New York, USA), and the co-investigators are J. Nutt (Oregon Health & Sciences University, Portland, Oregon, USA); C. Zabetian (University of Washington and Puget Sound Veterans Medical Center, Seattle, Washington, USA); S. Factor (Emory University, Atlanta, Georgia, USA); E. Molho (Albany Medical Center, Albany, New York, USA); and D. Higgins (Albany Medical Center and Albany Veterans Medical Center, Albany, New York, USA). Funding was provided by NIH grant R01NS36960. Genotyping was performed by the Genotyping Center at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Funding for genotyping was provided by NIH grant HHSN268200782096C. The NIH contract for the project is entitled 'High throughput genotyping for studying the genetic contributions to human disease'.

Support for the German cohort..

The German cohort was supported by the Alfried-Krupp-von-Bohlen-und-Hahlbach-Foundation (Graduate Schools of Tumour Biology and Free Radical Biology), the Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFG GRK840-E3/E4, MA 4115/1-2/3 and NI 1297/1-1), the Federal Ministry of Education and Research (BMBF GANI-MED 03152061A and BMBF 0314107) and the European Union (EU-FP-7; EPC-TM and EU-FP7-REGPOT-2010-1).

Author information

Author notes

    • Adam C Naj

    Present address: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Affiliations

  1. Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • David C Whitcomb
    • , Jessica LaRusch
    • , Randall E Brand
    • , Lidiya Orlichenko
    • , Andres Gelrud
    • , Georgios I Papachristou
    • , Vijay P Singh
    • , Adam Slivka
    • , Narcis Octavian Zarnescu
    • , Michael R O'Connell
    • , Michelle L Kienholz
    •  & Dhiraj Yadav
  2. Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • David C Whitcomb
    •  & Donna Stolz
  3. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.

    • David C Whitcomb
    • , F Yesim Demirci
    • , M Ilyas Kamboh
    • , M Michael Barmada
    •  & Bernie Devlin
  4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Alyssa M Krasinskas
    •  & Douglas J Hartman
  5. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Lambertus Klei
    • , Mary Ganguli
    • , Nadine M Melhem
    •  & Bernie Devlin
  6. Division of Gastroenterology and Liver Diseases, Pennsylvania State University, Hershey, Pennsylvania, USA.

    • Jill P Smith
  7. Department of Molecular and Clinical Cancer Medicine, National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

    • John P Neoptolemos
    • , Marianne Johnstone
    • , William Greenhalf
    •  & Robert Sutton
  8. Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.

    • Markus M Lerch
    • , Julia Mayerle
    • , Peter Simon
    •  & Frank Ulrich Weiss
  9. Aurora Health Care System, St. Luke's Medical Center, Milwaukee, Wisconsin, USA.

    • Matt Tector
    •  & Nalini M Guda
  10. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA.

    • Bimaljit S Sandhu
  11. Department of Medicine, Saint Louis University, St. Louis, Missouri, USA.

    • Samer Alkaade
  12. North Mississippi Medical Center, Tupelo, Mississippi, USA.

    • Stephen T Amann
  13. Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.

    • Michelle A Anderson
  14. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • James R Burke
    • , Kathleen A Welsh-Bohmer
    •  & John Baillie
  15. Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Peter A Banks
    •  & Darwin Conwell
  16. Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA.

    • Gregory A Coté
    •  & Stuart Sherman
  17. Digestive Disease Center, Medical University of South Carolina, Charleston, South Carolina, USA.

    • Peter B Cotton
    • , Robert A Hawes
    • , Christopher Lawrence
    •  & Joseph Romagnuolo
  18. Department of Medicine, University of Utah Health Science Center, Salt Lake City, Utah, USA.

    • James DiSario
  19. Department of Medicine/Biomedical Genetics Section, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Lindsay A Farrer
  20. Department of Medicine, University of Florida, Gainesville, Florida, USA.

    • Chris E Forsmark
  21. Department of Medicine, Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire, USA.

    • Timothy B Gardner
  22. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.

    • Jonathan L Haines
  23. Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA.

    • Jonathan L Haines
  24. Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA.

    • Michele Lewis
  25. Gertrude H Sergievsky Center, Department of Neurology, Columbia University, New York, New York, USA.

    • Christiane Reitz
    • , Badri N Vardarajan
    •  & Richard Mayeux
  26. Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York, USA.

    • Lawrence S Honig
    • , Christiane Reitz
    • , Badri N Vardarajan
    • , Jean Paul Vonsattel
    • , Jennifer Williamson
    •  & Richard Mayeux
  27. Meritus Medical Center, Hagerstown, Maryland, USA.

    • Mary E Money
  28. Department of Internal Medicine, Yale University and Griffin Hospital, Derby, Connecticut, USA.

    • Thiruvengadam Muniraj
  29. The John P Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.

    • Gary W Beecham
    • , John R Gilbert
    • , Kara L Hamilton-Nelson
    • , Eden R Martin
    • , Adam C Naj
    •  & Margaret A Pericak-Vance
  30. Dr John T Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA.

    • Gary W Beecham
    • , John R Gilbert
    • , Kara L Hamilton-Nelson
    • , Eden R Martin
    • , Adam C Naj
    •  & Margaret A Pericak-Vance
  31. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Laura B Cantwell
    • , Chiao-Feng Lin
    • , John Q Trojanowski
    • , Otto Valladares
    • , Vivianna M Van Deerlin
    • , Li-San Wang
    •  & Gerard D Schellenberg
  32. Department of Medicine, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • C Mel Wilcox
  33. Department of Epidemiology, Epidemiology Data Center, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Stephen R Wisniewski
  34. Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

    • Kathryn Roeder
  35. Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Marilyn S Albert
  36. Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.

    • Roger L Albin
    •  & Sid Gilman
  37. Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan, USA.

    • Roger L Albin
  38. Department of Neurology, University of California, Los Angeles, Los Angeles, California, USA.

    • Liana G Apostolova
    • , John M Ringman
    •  & Harry V Vinters
  39. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Steven E Arnold
  40. Department of Medicine (Genetics Program), Boston University, Boston, Massachusetts, USA.

    • Clinton T Baldwin
    •  & Gyungah Jun
  41. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA.

    • Robert Barber
  42. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.

    • Lisa L Barnes
    • , David A Bennett
    • , Julie A Schneider
    •  & Lei Yu
  43. Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA.

    • Lisa L Barnes
  44. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona, USA.

    • Thomas G Beach
  45. National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA.

    • Duane Beekly
  46. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

    • David A Bennett
  47. Department of Pathology, Northwestern University, Chicago, Illinois, USA.

    • Eileen H Bigio
  48. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • Thomas D Bird
  49. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Deborah Blacker
  50. Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.

    • Deborah Blacker
  51. Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

    • Adam Boxer
    • , Anna Karydas
    • , Bruce L Miller
    • , Howard J Rosen
    •  & William W Seeley
  52. Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.

    • Joseph D Buxbaum
  53. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.

    • Joseph D Buxbaum
    •  & Mary Sano
  54. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.

    • Joseph D Buxbaum
  55. Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA.

    • Nigel J Cairns
    •  & John C Morris
  56. University of South Florida (USF) Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA.

    • Chuanhai Cao
    • , Huntington Potter
    • , Ashok Raj
    •  & Amanda G Smith
  57. Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, USA.

    • Regina M Carney
  58. Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Steven L Carroll
    •  & Kenneth B Fallon
  59. Department of Neurology, University of Southern California, Los Angeles, California, USA.

    • Helena C Chui
    •  & Lon S Schneider
  60. Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • David G Clark
    • , Lindy E Harrell
    • , Daniel C Marson
    •  & Erik D Roberson
  61. Department of Neurology, University of California, Irvine, Irvine, California, USA.

    • David H Cribbs
    •  & Aimee Pierce
  62. Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, USA.

    • Elizabeth A Crocco
  63. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Carlos Cruchaga
    •  & Alison M Goate
  64. Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Carlos Cruchaga
    •  & Alison M Goate
  65. Department of Neurology, University of California, Davis, Sacramento, California, USA.

    • Charles DeCarli
    •  & John M Olichney
  66. Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California, USA.

    • Malcolm Dick
    •  & Wayne W Poon
  67. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.

    • Dennis W Dickson
    • , Nilufer Ertekin-Taner
    • , Neill R Graff-Radford
    •  & Steven G Younkin
  68. Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida, USA.

    • Ranjan Duara
  69. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.

    • Nilufer Ertekin-Taner
    •  & Neill R Graff-Radford
  70. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA.

    • Kelley M Faber
    • , Tatiana M Foroud
    • , Jill R Murrell
    •  & Andrew J Saykin
  71. Department of Neurology, Indiana University, Indianapolis, Indiana, USA.

    • Martin R Farlow
  72. Department of Psychiatry, New York University, New York, New York, USA.

    • Steven Ferris
    •  & Barry Reisberg
  73. CS Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

    • Matthew P Frosch
  74. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.

    • Douglas R Galasko
    • , Edward H Koo
    •  & Eliezer Masliah
  75. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.

    • Marla Gearing
  76. Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia, USA.

    • Marla Gearing
  77. Neurogenetics Program, University of California, Los Angeles, Los Angeles, California, USA.

    • Daniel H Geschwind
  78. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, USA.

    • Bernardino Ghetti
    • , Jill R Murrell
    •  & Salvatore Spina
  79. Department of Neurology, Emory University, Atlanta, Georgia, USA.

    • Jonathan D Glass
    • , James J Lah
    •  & Allan I Levey
  80. Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Robert C Green
  81. Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.

    • John H Growdon
    • , Bradley T Hyman
    •  & Rudolph E Tanzi
  82. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Hakon Hakonarson
  83. Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Ronald L Hamilton
  84. Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky, USA.

    • Elizabeth Head
  85. Department of Pathology, Duke University, Durham, North Carolina, USA.

    • Christine M Hulette
  86. Sanders-Brown Center on Aging, Department of Neurology, University of Kentucky, Lexington, Kentucky, USA .

    • Gregory A Jicha
  87. Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, California, USA.

    • Lee-Way Jin
    •  & Joshua W Miller
  88. Department of Biostatistics, Boston University, Boston, Massachusetts, USA.

    • Gyungah Jun
    •  & Lindsay A Farrer
  89. Department of Ophthalmology, Boston University, Boston, Massachusetts, USA.

    • Gyungah Jun
    • , Kathryn L Lunetta
    •  & Lindsay A Farrer
  90. University of Pittsburgh Alzheimer's Disease Research Center, Pittsburgh, Pennsylvania, USA.

    • M Ilyas Kamboh
    •  & Oscar L Lopez
  91. Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA.

    • Jeffrey A Kaye
    • , Patricia Kramer
    •  & Joseph F Quinn
  92. Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon, USA.

    • Jeffrey A Kaye
  93. Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, California, USA.

    • Ronald Kim
  94. Department of Neurology, Boston University, Boston, Massachusetts, USA.

    • Neil W Kowall
    • , Ann C McKee
    • , Robert A Stern
    •  & Lindsay A Farrer
  95. Department of Pathology, Boston University, Boston, Massachusetts, USA.

    • Neil W Kowall
    •  & Ann C McKee
  96. Department of Neuropsychology, University of California, San Francisco, San Francisco, California, USA.

    • Joel H Kramer
  97. Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA.

    • Patricia Kramer
  98. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Walter A Kukull
  99. Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, USA.

    • Frank M LaFerla
  100. Department of Pathology, University of Washington, Seattle, Washington, USA.

    • James B Leverenz
    • , Thomas J Montine
    •  & Joshua A Sonnen
  101. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.

    • Ge Li
    • , Elaine Peskind
    • , Murray Raskind
    •  & Debby W Tsuang
  102. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

    • Andrew P Lieberman
  103. Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA.

    • Constantine G Lyketsos
  104. Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA.

    • Wendy J Mack
  105. Department of Medicine–Pulmonary, New York University, New York, New York, USA.

    • Frank Martiniuk
  106. Department of Neurology, University of Miami, Miami, Florida, USA.

    • Deborah C Mash
  107. Department of Pathology, University of California, San Diego, La Jolla, California, USA.

    • Eliezer Masliah
  108. Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois, USA.

    • Marsel Mesulam
    •  & Sandra Weintraub
  109. Department of Pathology, University of Southern California, Los Angeles, California, USA.

    • Carol A Miller
  110. Department of Neurology, Washington University, St. Louis, Missouri, USA.

    • John C Morris
  111. Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Joseph E Parisi
  112. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Joseph E Parisi
  113. Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.

    • Ronald C Petersen
  114. Arizona Alzheimer's Consortium, Phoenix, Arizona, USA.

    • Eric M Reiman
  115. Banner Alzheimer's Institute, Phoenix, Arizona, USA.

    • Eric M Reiman
  116. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA.

    • Eric M Reiman
  117. Alzheimer's Disease Center, New York University, New York, New York, USA.

    • Barry Reisberg
  118. Department of Neurology, University of Texas Southwestern, Dallas, Texas, USA.

    • Roger N Rosenberg
  119. Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana, USA.

    • Andrew J Saykin
  120. Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, USA.

    • Julie A Schneider
  121. Department of Psychiatry, University of Southern California, Los Angeles, California, USA.

    • Lon S Schneider
  122. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Juan C Troncoso
  123. Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA.

    • Linda J Van Eldik
  124. Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Harry V Vinters
  125. Department of Psychiatry & Behavioral Sciences, Duke University, Durham, North Carolina, USA.

    • Kathleen A Welsh-Bohmer
  126. Department of Pathology, Oregon Health & Science University, Portland, Oregon, USA.

    • Randall L Woltjer
  127. Evelyn F McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida, USA.

    • Clinton B Wright
  128. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Chang-En Yu

Consortia

  1. Alzheimer's Disease Genetics Consortium

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Contributions

The writing group comprised A.M.K., B.D., D.C.W., J.L., L.K. and M.L.K. Project design, management and coordination were carried out by B.D., D.C.W., D.Y., J.P.N., M.M.B., M.M.L., N.M.M. and S.R.W. Sample collection and phenotyping were performed by A.G., A.S., B.S.S., C.E.F., C.L., C.M.W., D.C., D.C.W., D.Y., F.U.W., G.A.C., G.I.P., J.B., J.D., J.M., J.P.N., J.P.S., J.R., M.A.A., M.E.M., M.J., M.L., M.M.B., M.M.L., M.T., N.M.G., P.A.B., P.B.C., P.S., R.A.H., R.E.B., R.S., S.A., S.S., S.T.A., T.B.G., T.M. and W.G. Genotyping and expression studies were performed by A.M.K., D.J.H., D.S., G.D.S., J.L., J.L.H., J.P.S., L.A.F., L.O., M.A.P.-V., N.O.Z., R.M. and V.K.S. A.M.K. reviewed immunohistochemical staining. Statistical analysis was carried out by B.D., D.Y., K.R., L.K., M.M.B. and M.R.O.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David C Whitcomb or Bernie Devlin.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–10

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.2466

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