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Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Nature Genetics volume 44, pages 1349–1354 (2012)Cite this article

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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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Figure 1: Regional association plots for analysis of chronic and recurrent acute pancreatitis.
Figure 2: Expression and localization of claudin-2 in the human pancreas relative to rs12688220 genotype.

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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).

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Author notes

  1. Adam C Naj

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

  2. devlinbj@upmc.edu

Authors and 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. Department of Neurology, Gertrude H Sergievsky Center, Columbia University, New York, New York, USA

    Christiane Reitz, Badri N Vardarajan & Richard Mayeux

  26. Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, 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. Department of Molecular and Biomedical Pharmacology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA

    Elizabeth Head

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

    Christine M Hulette

  86. Department of Neurology, Sanders-Brown Center on Aging, 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. Department of Anatomy and Neurobiology, Sanders-Brown Center on Aging, 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. Department of Neurology, Evelyn F McKnight Brain Institute, 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

Authors
  1. David C Whitcomb
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  2. Jessica LaRusch
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Consortia

Alzheimer's Disease Genetics Consortium

  • Marilyn S Albert
  • , Roger L Albin
  • , Liana G Apostolova
  • , Steven E Arnold
  • , Clinton T Baldwin
  • , Robert Barber
  • , Lisa L Barnes
  • , Thomas G Beach
  • , Gary W Beecham
  • , Duane Beekly
  • , David A Bennett
  • , Eileen H Bigio
  • , Thomas D Bird
  • , Deborah Blacker
  • , Adam Boxer
  • , James R Burke
  • , Joseph D Buxbaum
  • , Nigel J Cairns
  • , Laura B Cantwell
  • , Chuanhai Cao
  • , Regina M Carney
  • , Steven L Carroll
  • , Helena C Chui
  • , David G Clark
  • , David H Cribbs
  • , Elizabeth A Crocco
  • , Carlos Cruchaga
  • , Charles DeCarli
  • , F Yesim Demirci
  • , Malcolm Dick
  • , Dennis W Dickson
  • , Ranjan Duara
  • , Nilufer Ertekin-Taner
  • , Kelley M Faber
  • , Kenneth B Fallon
  • , Martin R Farlow
  • , Steven Ferris
  • , Tatiana M Foroud
  • , Matthew P Frosch
  • , Douglas R Galasko
  • , Mary Ganguli
  • , Marla Gearing
  • , Daniel H Geschwind
  • , Bernardino Ghetti
  • , John R Gilbert
  • , Sid Gilman
  • , Jonathan D Glass
  • , Alison M Goate
  • , Neill R Graff-Radford
  • , Robert C Green
  • , John H Growdon
  • , Hakon Hakonarson
  • , Kara L Hamilton-Nelson
  • , Ronald L Hamilton
  • , Lindy E Harrell
  • , Elizabeth Head
  • , Lawrence S Honig
  • , Christine M Hulette
  • , Bradley T Hyman
  • , Gregory A Jicha
  • , Lee-Way Jin
  • , Gyungah Jun
  • , M Ilyas Kamboh
  • , Anna Karydas
  • , Jeffrey A Kaye
  • , Ronald Kim
  • , Edward H Koo
  • , Neil W Kowall
  • , Joel H Kramer
  • , Patricia Kramer
  • , Walter A Kukull
  • , Frank M LaFerla
  • , James J Lah
  • , James B Leverenz
  • , Allan I Levey
  • , Ge Li
  • , Chiao-Feng Lin
  • , Andrew P Lieberman
  • , Oscar L Lopez
  • , Kathryn L Lunetta
  • , Constantine G Lyketsos
  • , Wendy J Mack
  • , Daniel C Marson
  • , Eden R Martin
  • , Frank Martiniuk
  • , Deborah C Mash
  • , Eliezer Masliah
  • , Ann C McKee
  • , Marsel Mesulam
  • , Bruce L Miller
  • , Carol A Miller
  • , Joshua W Miller
  • , Thomas J Montine
  • , John C Morris
  • , Jill R Murrell
  • , Adam C Naj
  • , John M Olichney
  • , Joseph E Parisi
  • , Elaine Peskind
  • , Ronald C Petersen
  • , Aimee Pierce
  • , Wayne W Poon
  • , Huntington Potter
  • , Joseph F Quinn
  • , Ashok Raj
  • , Murray Raskind
  • , Eric M Reiman
  • , Barry Reisberg
  • , Christiane Reitz
  • , John M Ringman
  • , Erik D Roberson
  • , Howard J Rosen
  • , Roger N Rosenberg
  • , Mary Sano
  • , Andrew J Saykin
  • , Julie A Schneider
  • , Lon S Schneider
  • , William W Seeley
  • , Amanda G Smith
  • , Joshua A Sonnen
  • , Salvatore Spina
  • , Robert A Stern
  • , Rudolph E Tanzi
  • , John Q Trojanowski
  • , Juan C Troncoso
  • , Debby W Tsuang
  • , Otto Valladares
  • , Vivianna M Van Deerlin
  • , Linda J Van Eldik
  • , Badri N Vardarajan
  • , Harry V Vinters
  • , Jean Paul Vonsattel
  • , Li-San Wang
  • , Sandra Weintraub
  • , Kathleen A Welsh-Bohmer
  • , Jennifer Williamson
  • , Randall L Woltjer
  • , Clinton B Wright
  • , Steven G Younkin
  • , Chang-En Yu
  •  & Lei Yu

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.

Corresponding authors

Correspondence to David C Whitcomb or Bernie Devlin.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–10 (PDF 1828 kb)

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Whitcomb, D., LaRusch, J., Krasinskas, A. et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet 44, 1349–1354 (2012). https://doi.org/10.1038/ng.2466

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