Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort

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O R I G I N A L A R T I C L E¯ L I V E R , P A N C R E A S , A N D B I L I A R Y T R A C T

Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort Ellyn Dunbar1,2 • Phil J. Greer1 • Nadine Melhem3 • Samer Alkaade4,17 • Stephen T. Amann5 • Randall Brand1 • Gregory A. Cote´6,12 • Christopher E. Forsmark7 Timothy B. Gardner8 • Andres Gelrud1,9,18 • Nalini M. Guda10 • Jessica LaRusch1,19 • Michele D. Lewis11 • Jorge D. Machicado1,20 • Thiruvengadam Muniraj1,21 • Georgios I. Papachristou1,22 • Joseph Romagnuolo12,23 • Bimaljit S. Sandhu13,24 • Stuart Sherman6 • Charles M. Wilcox14 • Vikesh K. Singh15 • Dhiraj Yadav1 • David C. Whitcomb1,2,16 • For the NAPS2 study group



Received: 7 May 2020 / Accepted: 17 June 2020 Ó Japanese Society of Gastroenterology 2020

Abstract Background Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constantsevere pain experience in RAP/CP patients. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00535-020-01703-w) contains supplementary material, which is available to authorized users. & David C. Whitcomb [email protected] 1

Department of Medicine, University of Pittsburgh, Room 401.4, 3708 Fifth Ave, Pittsburgh, PA 15213, USA

2

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

3

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

4

Department of Medicine, St. Louis University, St. Louis, MO, USA

5

North Mississippi Medical Center, Tupelo, MS, USA

Study A retrospective study was done using North American Pancreatitis Study II (NAPS2) genotyped RAP and CP patients with completed case report forms (n = 1,357). Subjects were divided based on pattern of pain and pain severity as constant-severe pain (n = 787) versus not constant-severe pain (n = 570) to conduct a nested genome-wide association study. The association between

11

Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA

12

Present Address: Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

13

Department of Medicine, Medical College of Virginia, Richmond, VA, USA

14

Department of Medicine, University of Alabama At Birmingham, Birmingham, AL, USA

15

Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA

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Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, PA, USA

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Present Address: Mercy Clinic Gastroenterology, St. Louis, MO, USA

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Present Address: GastroHealth, Miami, FL, USA

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Present Address: Ariel Precision Medicine, Pittsburgh, PA, USA

20

Pre